Indolone derivatives having vascular damaging activity

ABSTRACT

This invention relates to the use of compounds of Formula (I) as vascular damaging agents: wherein X is selected from: —O—, —S—, —S(O)—, —S(O 2 )—, —N(R 5 )—, —C(O)—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O2)N(R 5 )—, or —N(R 5 )S(O 2 )—; R 1  is independently selected from: amino, halo, hydroxy, —OPO 3 H 2 , C 1-4 alkyl, or C 1-4 alkoxy, wherein the amino group is optionally substituted by an amino acid residue and the hydroxy group is optionally esterified; R 2  is selected from: hydrogen or C 1-4 alkyl; R 3  is selected from: hydrogen, halo, hydroxy, hydroxyC 1-4 alkyl, cyano, cyanoC 1-4 alkyl, carboxy, carboxyC 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkanoylC 1-4 alkyl, carbamoyl, carbamoylC 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, C 1-4 alkoxycarbonylC 1-4 alkyl, C 1-4 alkoxycarbonylamino, amino, N-C 1-4 alkylamino, NN-diC 1-4 alkylamino, aminoC 1-4 alkyl, N-C 1-4 alkylaminoC 1-4 alkyl, NN-diC 1-4 alkylaminoC 1-4 alkyl, ureido, or C 1-4 alkylureyleno; R 4  is independently selected from: C 1-4 alkyl, C 1-4 alkoxy or halo; R 5  is selected from: hydrogen or C 1-4 alkyl; n is 0 or 1; p is 0, 1, 2 or 3; and q is 0, 1 or 2; or a salt, pro-drug or solvate thereof. The invention also relates to novel compounds of Formula (I) and to processes for the preparation of compounds of Formula (I).

[0001] This invention relates to vascular damaging agents and theiruses. In particular it relates to certain novel compounds which may beof use as vascular damaging agents, to methods for preparing thecompounds, to their use as medicaments (including in methods for thetreatment of angiogenesis or disease states associated withangiogenesis) and to pharmaceutical compositions containing them. Theinvention also relates to the use of such compounds, and of certainanalogous, known compounds in the manufacture of medicaments for theproduction of anti-angiogenic and/or anti-vascular effects.

[0002] Normal angiogenesis plays an important role in a variety ofprocesses including embryonic development, wound healing and severalcomponents of female reproductive function. Undesirable or pathologicalangiogenesis has been associated with disease states including diabeticretinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi'ssarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16:57-66; Folkman, 1995, Nature Medicine 1: 27-31). Formation of newvasculature by angiogenesis is a key pathological feature of severaldiseases (J. Folkman, New England Journal of Medicine 333, 1757-1763(1995)). For example, for a solid tumour to grow it must develop its ownblood supply upon which it depends critically for the provision ofoxygen and nutrients; if this blood supply is mechanically shut off thetumour undergoes necrotic death. Neovascularisation is also a clinicalfeature of skin lesions in psoriasis, of the invasive pannus in thejoints of rheumatoid arthritis patients and of atherosclerotic plaques.Retinal neovascularisation is pathological in macular degeneration andin diabetic retinopathy.

[0003] Reversal of neovascularisation by damaging the newly-formedvascular endothelium is therefore expected to have a beneficialtherapeutic effect. Such vascular-damaging activity would clearly be ofvalue in the treatment of disease states associated with angiogenesissuch as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi'ssarcoma, haemangioma, acute and chronic nephropathies, atheroma,arterial restenosis, autoimmune diseases, acute inflammation,endometriosis, dysfunctional uterine bleeding and ocular diseases withretinal vessel proliferation.

[0004] Certain known compounds that cause selective destruction oftumour vasculature have been reported, in vitro and at non-cytotoxicconcentrations, to cause effects on proliferating endothelial cells, ie,cell detachment [Blakey D C et al, Proceedings of the AmericanAssociation for Cancer Research, 41, 329, 2000 abstract 2086] andchanges in cell shape [Davis P D et al, Proceedings of the AmericanAssociation for Cancer Research, 41, 329, 2000 abstract 2085; Chaplin DJ & Dougherty G J, Br J Cancer, 80, Suppl 1, 57-64, 1999]. It cantherefore be expected that these compounds will have damaging effects onnewly-formed vasculature, for example the vasculature of tumours. It canreasonably be predicted, for example, that they will be capable ofcausing selective destruction of tumour vasculature, both in vitro andin vivo. Destruction of tumour vasculature in turn leads to a reductionin tumour blood flow and to tumour cell death due to starvation ofoxygen and nutrients, ie, to anti-tumour activity [Davis P D et al;Chaplin D J & Dougherty G J; Blakey D C et al, all supra].

[0005] Compounds with this activity have also been described inInternational Patent Application WO 99/02166 (AngiogenePharmaceuticals), International Patent Application WO00/40529 (AngiogenePharmaceuticals) and International Patent Application WO 00/41669(Angiogene Pharmaceuticals).

[0006] We have identified a novel class of compounds with vasculardamaging activity. Thus, according to the first feature of the presentinvention there is provided the use of a compound of Formula (I) for themanufacture of a medicament to inhibit and/or reverse and/or alleviatesymptom of angiogenesis and/or any disease state associated withangiogenesis, wherein:

[0007] X is selected from: —O—, —S—, —S(O)—, —S(O₂)—, —N(R₅)—, —C(O)—,—C(O)N(R₅)—, —N(R₅)C(O)—, —S(O₂)N(R₅)—, or —N(R₅)S(O₂)—;

[0008] R₁ is independently selected from: amino, halo, hydroxy, —OPO₃H₂,C₁₋₄alkyl, or C₁₋₄alkoxy, wherein the amino group is optionallysubstituted by an amino acid residue and the hydroxy group is optionallyesterified;

[0009] R₂ is selected from: hydrogen or C₁₋₄alkyl;

[0010] R₃ is selected from: hydrogen, halo, hydroxy, hydroxyC₁₋₄alkyl,cyano, cyanoC₁₋₄alkyl, carboxy, carboxyC₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkanoylC₁₋₄alkyl, carbamoyl, carbamoylC₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylC₁₋₄alkyl,C₁₋₄alkoxycarbonylamino, amino, N-C₁₋₄alkylamino, N,N-diC₁₋₄alkylamino,aminoC₁₋₄alkyl, N-C₁₋₄alkylaminoC₁₋₄alkyl,N,N-diC₁₋₄alkylaminoC₁₋₄alkyl, ureido, or C₁₋₄alkylureyleno;

[0011] R₄ is independently selected from: C₁₋₄alkyl, C₁₋₄alkoxy or halo;

[0012] R₅ is selected from: hydrogen or C₁₋₄alkyl;

[0013] n is 0 or 1;

[0014] p is 0, 1, 2 or 3; and

[0015] q is 0, 1 or 2;

[0016] or a salt, pro-drug or solvate thereof.

[0017] Whilst pharmaceutically acceptable salts of compounds of theinvention are preferred, other non-pharmaceutically acceptable salts ofcompounds of the invention may be useful in the preparation ofpharmaceutically-acceptable salts of compounds of the invention.

[0018] According to a further aspect of the first feature of theinvention there is provided a method of treatment, in a warm-bloodedanimal, to inhibit and/or reverse and/or alleviate symptom ofangiogenesis and/or any disease state associated with angiogenesiscomprising administering to said warm-blooded animal a therapeutically(including prophylactically) effective amount of a compound of Formula(I), or a salt, pro-drug or solvate thereof.

[0019] Preferably a warm-blooded animal is a human.

[0020] According to a further aspect of the first feature of theinvention there is provided a pharmaceutical composition comprising acompound of Formula (I), or a pharmaceutically-acceptable salt, pro-drugor solvate thereof, in admixture with a pharmaceutically-acceptablediluent or carrier, to inhibit and/or reverse and/or alleviate symptomof angiogenesis and/or any disease state associated with angiogenesis.

[0021] For the avoidance of doubt when p is 0, all positions on thephenyl ring are substituted by hydrogen and when q is 0 all positions onthe aromatic ring of the oxindole ring are substituted by hydrogenexcept for the position to which the ‘(R₁)_(p)-Phenyl-(CH₂)_(n)—X—’group is attached.

[0022] For the avoidance of doubt the use of the term (R₁)_(p) when p isbetween 1 and 3, means that there are 1, 2 or 3 R¹ substituents on thephenyl ring, which when p is 2 or 3 can be the same group or differentgroups. For example, where (R₁)_(p) is 3-chloro-4-methoxy then p is 2and the phenyl ring has a chloro group at the 3-position and a methoxygroup at the 4-position, in relation to the —(CH₂)_(n)X— group, and forexample, when (R₁)_(p) is di-halo, then p is 2 and the phenyl ring hastwo halo substituents which may be the same group or different groups,wherein the halo groups occupy 2 positions on the phenyl ring.

[0023] In this specification the generic term ‘alkyl’ includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as ‘propyl’ are specific for thestraight-chain version only and references to individual branched-chainalkyl groups such as ‘isopropyl’ are specific for the branched-chainversion only. An analogous convention applies to other generic terms.

[0024] The term halo refers to fluoro, chloro, bromo or iodo.

[0025] The term carbamoyl refers to —C(O)NH₂.

[0026] An amino acid residue is defined as that derived form thecoupling of an L-amino acid with an amino group via an amide bond. Thisbond can either be formed via a carboxylate group on the amino acidbackbone or via a side chain carboxylate group, preferably viacarboxylate group on the amino acid backbone. Amino acid residuesinclude those derived from natural and non-natural amino acids,preferably natural amino acids and include α-amino acids, β-amino acidsand γ-amino acids. For the avoidance of doubt an amino acids includethose with the generic structure:

[0027] where R is the amino acid side chain: The definition of aminoacid also includes amino acid analogues which have additional methylenegroups within the amino acid backbone, for example β-alanine.

[0028] Preferred amino acids include glycine, alanine, valine, leucine,isoleucine, methionine, proline, phenylalanine, tryptophan, serine,threonine, cysteine, tyrosine, asparaginine, glutamine, aspartic acid,glutamic acid, lysine, arginine, histidine, β-alanine and ornithine.More preferred amino acids include glutamic acid, serine, threonine,arginine, glycine, alanine, β-alanine and lysine. Especially preferredamino acids include glutamic acid, serine, and glycine.

[0029] Preferably esterifying groups at R₁ are esterifying groups whichincrease the solubility of the molecule in water at a pH ofapproximately pH=7. Such groups included groups with ionisable groups,such as acidic functions or basic functions and groups containing ahydrophilic function. Basic functions include: amino, morpholino,piperidino, piperazino, pyrrolidino, amino acids and imidazolino. Acidicfunctions include: carboxy, sulphonic acid, phosphate, sulphate and acidmimetics such as tetrazolyl. Hydrophilic groups include hydroxyl.

[0030] Preferred R₁ groups wherein hydroxy is esterfied include:C₁₋₆alkanoyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy,heteroarylcarbonyloxy wherein the R₁ group is optionally substitutedwith between 1 and 3 groups selected from C₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkanoylC₁₋₄alkyl, C₁₋₄alkanoylheterocyclyl, hydroxy,hydroxyC₁₋₄alkyl, carboxy, carboxyphenyl, phosphono, phosphonoC₁₋₄alkyl,amino, aminoC₁₋₄alkyl, N-C₁₋₄alkylamino, N,N-diC₁₋₄alkylamino,carbamoyl, carbamoylC₁₋₄alkyl, heterocyclyl, heterocyclylC₁₋₄alkyl,heterocyclylcarbonyl, heterocyclC₁₋₄alkanoylamino,carbamoylheterocyclyl, [wherein optional substituents comprisingheterocyclyl are optionally further substituted by C₁₋₄alkyl,hydroxyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkanoyl and formyl, whereinthe carbamoyl and amino optional substituents are optionally furtherN-substituted by, C₁₋₄alkyl, di-C₁₋₄alkyl, hydroxyC₁₋₄alkyl,di-(hydroxyC₁₋₄alkyl), carboxyC₁₋₄alkyl, and wherein the amino group isoptionally substituted by an amino acid residue] with the proviso thatwhen R₁ is C₁₋₆alkanoyloxy or arylcarbonyloxy R₁ is not unsubstitutedand R₁ is not substituted by C₁₋₄alkyl.

[0031] More preferred R₁ groups wherein hydroxy is esterfied include:carboxypentanoyloxy,

[0032] 4-carboxyphenylpropanoyloxy4-(N-methylpiperizin-1-ylethyl)phenylcarbonyloxy,

[0033] 4-(piperizin-1-ylethyl)phenylcarbonyloxy,4-[N-di-(hydroxyethyl)aminomethyl]phenylcarbonyloxy,

[0034] 3-(N-acetylpiperizin-1-ylethyl)phenylcarbonyloxy,

[0035] 3-[N-di-(hydroxyethyl)aminomethyl]phenylcarbonyloxy,

[0036] 4-(N-methylpiperizin-1-ylpropanoylamino)phenylcarbonyloxy,

[0037] N-methylpiperizin-1-ylcarbonylpropanoyloxy,

[0038] N-di-(hydroxyethyl)aminocarbonylpropanoyloxy,piperizin-1-ylcarbonylpropanoyloxy,

[0039] (N-acetylpiperizin-1-yl)carbonylpropanoyloxy,(N-di-(hydroxyethyl)aminocarbonylpropanoyloxy, and4(piperizin-1-ylmethyl)phenylcarbonyloxy.

[0040] Further preferred R₁ groups wherein hydroxy is esterfied include:

[0041] 4-(N-methylpiperizin-1-ylpropanoylamino)phenylcarbonyloxy,

[0042] N-methylpiperizin-1-ylcarbonylpropanoyloxy and

[0043] N-di-(hydroxyethyl)aminocarbonylpropanoyloxy.

[0044] Examples of C₁₋₄alkyl include methyl, ethyl, propyl, isopropyl,sec-butyl and tert-butyl, examples of hydroxyC₁₋₄alkyl includehydroxymethyl, hydroxyethyl and hydroxypropyl, examples ofaminoC₁₋₄alkyl include aminomethyl, aminoethyl or aminopropyl, examplesof cyanoC₁₋₄alkyl include cyanomethyl, cyanoethyl and cyanopropyl,examples of carboxyC₁₋₄alkyl include carboxymethyl, carboxyethyl orcarboxypropyl, examples of carbamoylC₁₋₄alkyl includeaminocarbonylmethyl, aminocarbonylethyl and aminocarbonypropyl, examplesof C₁₋₄alkoxy include methoxy, ethoxy and propoxy, examples ofC₁₋₄alkoxycarbonyl include methoxycarbonyl, tert-butoxycarbonyl,ethoxycarbonyl and propoxycarbonyl, examples ofC₁₋₄alkoxycarbonylC₁₋₄alkyl include methoxycarbonylmethyl,tert-butoxycarbonylethyl, ethoxycarbonylmethyl and propoxycarbonylethyl,examples of C₁₋₄alkoxycarbonylamio include methoxycarbonylamino andt-butoxycarbonylamino, examples of C₁₋₄alkanoyl include acetyl,ethylcarbonyl and butylcarbonyl, examples of N-C₁₋₄alkylamino includeN-methylamino and N-ethylamino, and examples of N,N-diC₁₋₄alkylaminoinclude N,N-dimethylamino, N,N-diethylamino and N-methyl-N-ethylamino,examples of N-C₁₋₄alkylaminoC₁₋₄alkyl include N-methylaminomethyl andN-ethylaminoethyl, examples of N,N-di-C₁₋₄alkylaminoC₁₋₄alkyl includeN,N-dimethylaminomethyl and N-methyl-N-ethylaminomethyl, examples ofC₁₋₄alkylureyleno include methylureyleno, ethylureyleno orpropylureyleno.

[0045] A suitable pharmaceutically-acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a carbazole derivative of theinvention which is sufficiently acidic is an alkali metal salt, forexample a sodium or potassium salt, an alkaline earth metal salt, forexample a calcium or magnesium salt, an ammonium salt or a salt with anorganic base which affords a physiologically acceptable cation, forexample a salt with methylamine, dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0046] The compounds of the Formula (I) may be administered in the formof a pro-drug which is broken down in the human or animal body to give acompound of the Formula (I). Examples of pro-drugs include in-vivohydrolysable esters of a compound of the Formula (I).

[0047] Various forms of prodrugs are known in the art. For examples ofsuch prodrug derivatives, see:

[0048] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985)and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, etal. (Academic Press, 1985);

[0049] b) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application ofProdrugs”, by H. Bundgaard p. 113-191 (1991);

[0050] c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

[0051] d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77,285 (1988); and

[0052] e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

[0053] An in-vivo hydrolysable ester of a compound of the Formula (I)containing carboxy or hydroxy group is, for example, apharmaceutically-acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically-acceptable esters for carboxy include C₁₋₆alkoxymethylesters for example methoxymethyl, C₁₋₆alkanoyloxymethyl esters forexample pivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters.

[0054] An in-vivo hydrolysable ester of a compound of the Formula (I)containing a hydroxy group includes inorganic esters such as phosphateesters (including phosphoramidic cyclic esters) and α-acyloxyalkylethers and related compounds which as a result of the in-vivo hydrolysisof the ester breakdown to give the parent hydroxy group/s. Examples ofα-acyloxyalkyl ethers include acetoxymethoxy and2,2-dimethylpropionyloxy-methoxy. A selection of in-vivo hydrolysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl.

[0055] It is to be understood that, insofar as certain of the compoundsin the different features of the invention may exist in optically activeor racemic forms by virtue of one or more asymmetric carbon atoms, theinvention includes in its definition any such optically active orracemic form which possesses the property of inhibiting and/or reversingand/or alleviating the symptoms of angiogenesis and/or any diseasestates associated with angiogenesis. The synthesis of optically activeforms may be carried out by standard techniques of organic chemistrywell known in the art, for example by synthesis from optically activestarting materials or by resolution of a racemic form. Similarly,activity of these compounds may be evaluated using the standardlaboratory techniques referred to hereinafter.

[0056] The invention also relates to any and all tautomeric forms of thecompounds of the different features of the invention that possess theproperty of inhibiting and/or reversing and/or alleviating the symptomsof angiogenesis and/or any disease states associated with angiogenesis.

[0057] It will also be understood that certain compounds of the presentinvention may exist in solvated, for example hydrated, as well asunsolvated forms. It is to be understood that the present inventionencompasses all such solvated forms which possess the property of theproperty of inhibiting and/or reversing and/or alleviating the symptomsof angiogenesis and/or any disease states associated with angiogenesis.

[0058] According to a second feature of the invention there is providedthe use of a compound of Formula (II) as a medicament:

[0059] X is selected from: —O—, —S—, —S(O)—, —S(O₂)—, —N(R₅)—, —C(O)—,—C(O)N(R₅)—, —N(R₅)C(O)—, —S(O₂)N(R₅)—, or —N(R₅)S(O₂)—;

[0060] R₁ is independently selected from: amino, halo, hydroxy, —OPO₃H₂,C₁₋₄alkyl, or C₁₋₄alkoxy, wherein the amino group is optionallysubstituted by an amino acid residue and the hydroxy group is optionallyesterified;

[0061] R₂ is selected from: hydrogen or C₁₋₄aalkyl;

[0062] R₃ is selected from: hydrogen, halo, hydroxy, hydroxyC₁₋₄alkyl,cyano, cyanoC₁₋₄alkyl, carboxy, carboxyC₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkanoylC₁₋₄alkyl, carbamoyl, carbamoylC₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylC₁₋₄alkyl,C₁₋₄alkoxycarbonylamino, amino, N-C₁₋₄alkylamino, NN-diC₁₋₄alkylamino,aminoC₁₋₄alkyl, N-C₁₋₄alkylaminoC₁₋₄alkyl, NN-diC₁₋₄alkylaminoC₁₋₄alkyl,ureido, or C₁₋₄alkylureyleno;

[0063] R₄ is independently selected from: C₁₋₄alkyl, C₁₋₄alkoxy or halo;

[0064] R₅ is selected from: hydrogen or C₁₋₄alkyl;

[0065] n is 0 or 1;

[0066] p is 1, 2 or 3; and

[0067] q is 0, 1 or 2;

[0068] with the proviso that:

[0069] (i) when p is 1, R₁ cannot be halo or methyl, and when p is 2,(R₁)_(p) cannot be di-halo or di-methyl;

[0070] (ii) when X is —S(O₂)N(R₅)—, —N(R₅)S(O₂)—, —N(R₅)C(O)— or —C(O)—,n is 0 or 1, R₂ is hydrogen, R₃ is hydrogen, q is 0 or q is 1 and R₄ is5-chloro and R⁵is hydrogen, then (R₁)_(p) cannot be 2-methoxy,3-methoxy, 4-methoxy, 4-nitro, 4-hydroxy, 4-amino, 3-chloro-4-methoxy or3-chloro4-ethoxy; and

[0071] (ii) when X is linked at the 7-position of the oxindole ring, Xis —O—, n is 0, R₂ is hydrogen, R₃ is hydrogen or methyl and q is 0,then (R₁)_(p) cannot be 2-methoxy, 2-amino, or 3,4,5-tri-methoxy;or apharmaceutically-acceptable salt, prodrug or solvate thereof.

[0072] According to a further aspect of the second feature of theinvention there is provided a compound of Formula (IIa):

[0073] wherein X, R¹, R², R³, R⁴, R⁵, n, p and q are as defined for acompound of Formula (II); with the proviso that:

[0074] (i) when p is 1, R₁ cannot be halo or methyl, and when p is 2,(R₁)_(p) cannot be di-halo or di-methyl;

[0075] (ii) when X is —S(O₂)N(R₅)—, —N(R₅)S(O₂)—, —N(R₅)C(O)— or —C(O)—,n is 0 or 1, R₂ is hydrogen, R₃ is hydrogen, q is 0 or q is 1 and R₄ is5-chloro and R⁵ is hydrogen, then (R₁)_(p) cannot be 2-methoxy,3-methoxy, 4-methoxy, 4-nitro, 4-hydroxy, 4-amino, 3-chloro4-methoxy or3-chloro-4-ethoxy; and

[0076] (ii) when X is linked at the 7-position of the oxindole ring, Xis —O—, n is 0, R₂ is hydrogen, R₃ is hydrogen or methyl and q is 0,then (R₁)_(p) cannot be 2-methoxy, 2-amino, or 3,4,5-tri-methoxy;

[0077] or a pharmaceutically-acceptable salt, pro-drug or solvatethereof.

[0078] According to a further aspect of the second feature of theinvention there is provided a pharmaceutical composition comprising acompound of Formula (II) or Formula (IIa), orpharmaceutically-acceptable salt, pro-drug or solvate.

[0079] According to a further aspect of the second feature of theinvention there is provided a pharmaceutical composition comprising acompound of Formula (II) or Formula (IIa), or apharmaceutically-acceptable salt, pro-drug or solvate thereof, inadmixture with a pharmaceutically-acceptable diluent or carrier.

[0080] According to a third feature of the invention there is provided acompound of Formula (III), wherein:

[0081] X is selected from: —S—, —S(O)—, or —S(O₂)—;

[0082] R₁ is independently selected from: amino, halo, hydroxy, —OPO₃H₂,C₁₋₄alkyl, or C₁₋₄alkoxy, wherein the amino group is optionallysubstituted by an amino acid residue and the hydroxy group is optionallyesterified;

[0083] R₂ is selected from: hydrogen or C₁₋₄alkyl;

[0084] R₃ is selected from: hydrogen, halo, hydroxy, hydroxyC₁₋₄alkyl,cyano, cyanoC₁₋₄alkyl, carboxy, carboxyC₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkanoylC₁₋₄alkyl, carbamoyl, carbamoylC₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylC₁₋₄alkyl,C₁₋₄alkoxycarbonylamino, amino, N-C₁₋₄alkylamino, NN-diC₁₋₄alkylamino,aminoC₁₋₄alkyl, N-C₁₋₄alkylaminoC₁₋₄alkyl, NN-diC₁₋₄alkylaminoC₁₋₄alkyl,ureido, or C₁₋₄alkylureyleno;

[0085] R₄ is independently selected from: C₁₋₄alkyl, C₁₋₄alkoxy or halo;

[0086] n is 0 or 1;

[0087] p is 0, 1, 2 or 3; and

[0088] q is 0, 1 or 2;

[0089] with the proviso that the following compounds are excluded:

[0090] 7-(phenylsulfanyl)-1,3-dihydro-2H-indol-2-one;

[0091] 7-(2-chlorophenylsulfanyl)-1,3-dihydro-2H-indol-2-one;

[0092] 7-(4-chlorophenylsulfanyl)-1,3-dihydro-2H-indol-2-one;

[0093] 7-(benzylsulfanyl)-1,3-dihydro-2H-indol-2one;

[0094] 7-(phenylsulfinyl)-1,3-dihydro-2H-indol-2-one;

[0095] 7-(2-chlorophenylsulfinyl)-1,3-dihydro-2H-indol-2-one;

[0096] 7-(4-chlorophenylsulfinyl)-1,3-dihydro-2H-indol-2-one;

[0097] 7-(phenylsulfonyl)-1,3-dihydro-2H-indol-2-one; and

[0098] 7-(4chlorophenylsulfonyl)-1,3-dihydro-2H-indol-2-one;

[0099] or pharmaceutically-acceptable salt, pro-drug or solvate thereof.

[0100] According to a further aspect of the third feature of theinvention there is provided a compound of Formula (III); as definedabove, with the proviso that:

[0101] when —(CH₂)_(n)X— is linked at the 7-position of the oxindolering, n is 0 or 1, R₂ and R₃ are each independently hydrogen and q is 0,then p cannot be 0 and (R₁)_(p) cannot be 2-chloro or 4-chloro;

[0102] or pharmaceutically-acceptable salt, pro-drug or solvate thereof.

[0103] According to a fourth feature of the invention there is provideda compound of Formula (IV), wherein:

[0104] R₁ is independently selected from: amino, halo, hydroxy, —OPO₃H₂,C₁₋₄alkyl, or C₁₋₄alkoxy, wherein the amino group is optionallysubstituted by an amino acid residue and the hydroxy group is optionallyesterified;

[0105] R₂ is selected from: hydrogen or C₁₋₄alkyl;

[0106] R₃ is selected from: hydrogen, halo, hydroxy, hydroxyC₁₋₄alkyl,cyano, cyanoC₁₋₄alkyl, carboxy, carboxyC₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkanoylC₁₋₄alkyl, carbamoyl, carbamoylC₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylC₁₋₄alkyl,C₁₋₄alkoxycarbonylamino, amino, N-C₁₋₄alkylamino, NN-diC₁₋₄alkylamino,aminoC₁₋₄alkyl, N-C₁₋₄alkylaminoC₁₋₄alkyl, NN-diC₁₋₄alkylamihoC₁₋₄alkyl,ureido, or C₁₋₄alkylureyleno;

[0107] R₄ is independently selected from: C₁₋₄alkyl, C₁₋₄alkoxy or halo;

[0108] R₅ is selected from: hydrogen or C₁₋₄alkyl;

[0109] n is 0 or 1;

[0110] p is 0, 1, 2 or 3; and

[0111] q is 0, 1 or 2;

[0112] with the proviso that the following compounds are excluded:

[0113] 5-(benzylamino)-1,3-dihydro-2H-indol-2-one;

[0114] 7-anilino-1,3-dihydro-2H-indol-2-one;

[0115] 7-(2-chloroanilino)-1,3-dihydro-2H-indol-2-one; and

[0116] 7-(4-chloroanilino)-1,3-dihydro-2H-indol-2-one;

[0117] or pharmaceutically-acceptable salt, pro-drug or solvate thereof.

[0118] According to a further aspect of the fourth feature of theinvention there is provided a compound of Formula (IV), as definedabove, with the proviso that:

[0119] (i) when —(CH₂)_(n)N(R₅)— is linked at the 5-position of theoxindole ring, n is 1, R₂ and R₃ are each independently hydrogen and qis 0, then p cannot be 0; and

[0120] (ii) when —(CH₂)_(n)N(R₅)— is linked at the 7-position of theoxindole ring, n is 0, R₂ and R₃ are each independently hydrogen and qis 0, then p cannot be 0 and (R₁)_(p) cannot be 2-chloro or 4-chloro;

[0121] or pharmaceutically-acceptable salt, pro-drug or solvate thereof.

[0122] According to a fifth feature of the invention there is provided acompound of Formula (V), wherein:

[0123] R₁ is independently selected from: amino, halo, hydroxy, —OPO₃H₂,C₁₋₄alkyl, or C₁₋₄alkoxy, wherein the amino group is optionallysubstituted by an amino acid residue and the hydroxy group is optionallyesterified;

[0124] R₂ is selected from: hydrogen or C₁₋₄alkyl;

[0125] R₃ is selected from: hydrogen, halo, hydroxy, hydroxyC₁₋₄alkyl,cyano, cyanoC₁₋₄alkyl, carboxy, carboxyC₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkanoylC₁₋₄alkyl, carbamoyl, carbamoylC₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylC₁₋₄alkyl,C₁₋₄alkoxycarbonylamino, amino, N-C₁₋₄alkylamino, NN-diC₁₋₄alkylamino,aminoC₁₋₄alkyl, N-C₁₋₄alkylaminoC₁₋₄alkyl, NN-diC₁₋₄alkylaminoC₁₋₄alkyl,ureido, or C₁₋₄alkylureyleno;

[0126] R₄ is independently selected from: C₁₋₄alkyl, C₁₋₄alkoxy or halo;

[0127] R₅ is selected from: hydrogen or C₁₋₄alkyl;

[0128] n is 0 or 1;

[0129] p is 0, 1, 2 or 3; and

[0130] q is 0, 1 or 2;

[0131] with the proviso that:

[0132] (i) when —(CH₂)_(n)O— is linked at the 4-position of the oxindolering, n is 0, p is 0 and R₂ and R₃ are each independently hydrogen and qis 1 then R₄ cannot be 7-chloro;

[0133] (ii) when —(CH₂)_(n)O— is linked at the 5-position of theoxindole ring, n is 0 or 1, R₂ is hydrogen or methyl, R₃ is hydrogen andq is 0, then p cannot be 0 and (R₁)_(p) cannot be 2-chloro or chloro;

[0134] (iii) when —(CH₂)_(n)O— is linked at the 6-position of theoxindole ring, n is 1, p is 0, R₂ is hydrogen or methyl, R₃ is hydrogenand q is 1 then R₄ cannot be 5-methoxy; and

[0135] (iv) when —(CH₂)_(n)O— is linked at the 7-position of theoxindole ring, n is 0 or 1, R₂ is hydrogen or methyl, R₃ is hydrogen andq is 0, then p cannot be 0 and (R₁)_(p) cannot be 2-chloro, 2-fluoro,2-amino, 2,6-dichloro or 3,4,5-trimethoxy;

[0136] or pharmaceutically-acceptable salt, pro-drug or solvate thereof.

[0137] According to the sixth feature of the invention there is provideda compound of Formula (VI), wherein:

[0138] R₁ is independently selected from: amino, halo, hydroxy, —OPO₃H₂,C₁₋₄alkyl, or C₁₋₄alkoxy, wherein the amino group is optionallysubstituted by an amino acid residue and the hydroxy group is optionallyesterified;

[0139] R₂ is selected from: hydrogen or C₁₋₄alkyl;

[0140] R₃ is selected from: hydrogen, halo, hydroxy, hydroxyC₁₋₄alkyl,cyano, cyanoC₁₋₄alkyl, carboxy, carboxyC₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkanoylC₁₋₄alkyl, carbamoyl, carbamoylC₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylC₁₋₄alkyl,C₁₋₄alkoxycarbonylamino, amino, N-C₁₋₄alkylamino, NN-diC₁₋₄alkylamino,aminoC₁₋₄alkyl, N-C₁₋₄alkylaminoC₁₋₄alkyl, NN-diC₁₋₄alkylaminoC₁₋₄alkyl,ureido, or C₁₋₄alkylureyleno;

[0141] R₄ is independently selected from: C₁₋₄alkyl, C₁₋₄alkoxy or halo;

[0142] R₅ is selected from: hydrogen or C₁₋₄alkyl;

[0143] n is 0 or 1;

[0144] p is 0, 1, 2 or 3; and

[0145] q is 0, 1 or 2;

[0146] with the proviso that:

[0147] (i) when —(CH₂)_(n)C(O)— is linked at the 4-position of theoxindole ring, n is 0, p is 0, R₂ and R₃ are each independentlyhydrogen, then q cannot be 0;

[0148] (ii) when —(CH₂)_(n)C(O)— is linked at the 5-position of theoxindole ring, n is 0, R₂ is hydrogen or ethyl, R₃ is hydrogen ormethoxycarbonyl and q is 0, then p cannot be 0 and (R₁)_(p) cannot be4-methyl, 4-chloro or 4-fluoro;

[0149] (iii) when —(CH₂)_(n)C(O)— is linked at the 6-position of theoxindole ring, n is 0, R₂ is hydrogen or ethyl, R₃ is hydrogen and q is0, then p cannot be 0 and (R₁)_(p) cannot be 4-methyl, 4-methoxy or4-chloro;

[0150] (iv) when —(CH₂)_(n)C(O)— is linked at the 7-position of theoxindole ring, n is 0, R₂ is hydrogen, methyl or ethyl, R₃ is hydrogen,hydroxy, methoxycarbonyl, or ethoxycarbonyl, and q is 0 or q is 1 and R₄is 4-methyl, 5-methyl, 6-methyl, 5-methoxy, 5-chloro, 6-chloro, 5-bromoor 5-fluoro, then p cannot be 0 and (R₁)_(p) cannot be 2-methyl,4-methyl, 4-methoxy, 4-hydroxy, 4-chloro, 4-bromo, 2-fluoro, 4-fluoro,4-iodo, 2,4-dimethyl, 2,4-dichloro, 3,4-dichloro or 2-chloro-4-bromo;

[0151] or a salt, pro-drug or solvate thereof.

[0152] According to the seventh feature of the invention there isprovided a compound of Formula (VII), wherein:

[0153] X is selected from: —C(O)N(R₅)— or —N(R₅)C(O)—;

[0154] R₁ is independently selected from: amino, halo, hydroxy, —OPO₃H₂,C₁₋₄alkyl, or C₁₋₄alkoxy, wherein the amino group is optionallysubstituted by an amino acid residue and the hydroxy group is optionallyesterified;

[0155] R₂ is selected from: hydrogen or C₁₋₄alkyl;

[0156] R₃ is selected from: hydrogen, halo, hydroxy, hydroxyC₁₋₄alkyl,cyano, cyanoC₁₋₄alkyl, carboxy, carboxyC₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkanoylC₁₋₄alkyl, carbamoyl, carbamoylC₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylC₁₋₄alkyl,C₁₋₄alkoxycarbonylamino, amino, N-C₁₋₄alkylamino, NN-diC₁₋₄alkylamino,aminoC₁₋₄alkyl, N-C₁₋₄alkylaminoC₁₋₄alkyl, NN-diC₁₋₄alkylaminoC₁₋₄alkyl,ureido, or C₁₋₄alkylureyleno;

[0157] R₄ is independently selected from: C₁₋₄alkyl, C₁₋₄alkoxy or halo;p1 R₅ is selected from: hydrogen or C₁₋₄alkyl;

[0158] n is 0 or 1;

[0159] p is 0, 1, 2 or 3; and

[0160] q is 0, 1 or 2;

[0161] with the proviso that:

[0162] (i) when X is —N(R₅)_(n)C(O)— linked at the 4-position of theoxindole ring, n is 0, R₂, R₃ and R₅ are each independently hydrogen andq is 0, then (R₁)_(p) cannot be 4-methoxy, 3-chloro-4-methoxy or3-chloro-4-ethoxy; and

[0163] (ii) when X is —C(O)N(R₅)_(n)— linked at the 5-position of theoxindole ring, n is 0, p is 0, R₂, R₃ and R₅ are each independentlyhydrogen, then q cannot be 0 or a salt, pro-drug or solvate thereof.

[0164] According to the eight feature of the invention there is provideda compound of Formula (VIII), wherein:

[0165] X is selected from: —S(O₂)N(R₅)— or —N(R₅)S(O₂)—;

[0166] R₁ is independently selected from: amino, halo, hydroxy, —OPO₃H₂,C₁₋₄alkyl, or C₁₋₄alkoxy, wherein the amino group is optionallysubstituted by an amino acid residue and the hydroxy group is optionallyesterified;

[0167] R₂ is selected from: hydrogen or C₁₋₄alkyl;

[0168] R₃ is selected from: hydrogen, halo, hydroxy, hydroxyC₁₋₄alkyl,cyano, cyanoC₁₋₄alkyl, carboxy, carboxyC₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkanoylC₁₋₄alkyl, carbamoyl, carbamoylC₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylC₁₋₄alkyl,C₁₋₄alkoxycarbonylamino, amino, N-C₄alkylamino, NN-diC₁₋₄alkylamino,aminoC₁₋₄alkyl, N-C₁₋₄alkylaminoC₁₋₄alkyl, NN-diC₁₋₄alkylaminoC₁₋₄alkyl,ureido, or C₁₋₄alkylureyleno;

[0169] R₄ is independently selected from: C₁₋₄alkyl, C₁₋₄alkoxy or halo;

[0170] R₅ is selected from: hydrogen or C₁₋₄alkyl;

[0171] n is 0 or 1;

[0172] p is 0, 1, 2 or 3; and

[0173] q is 0, 1 or 2;

[0174] with the proviso that the following compounds are excluded:

[0175] 4-(4-methylbenzenesulphonamido)-1,3-dihydro-2H-indol-2-one;

[0176] 5-benzenesulphonamido-1,3-dihydro-2H-indol-2-one;

[0177] 5-(4-methylbenzenesulphonamido)-1,3-dihydro-2H-indol-2-one;

[0178]N-methyl-5-(4-methylbenzenesulphonamido)-1,3-dihydro-2H-indol-2-one;

[0179]N-methyl-5-(N-methyl-4-methylbenzenesulphonamido)-1,3-dihydro-2H-indol-2-one;

[0180] 6-(4-methylbenzenesulphonamido)-1,3-dihydro-2H-indol-2-one;

[0181]6-(N-methyl-4-methylbenzenesulphonamido)-1,3-dihydro-2H-indol-2-one;

[0182] 7-(4-methylbenzenesulphonamido)-1,3-dihydro-2H-indol-2-one;

[0183] 6-(4-methoxybenzenesulphonamido)-1,3-dihydro-2H-indol-2-one;

[0184] 6-(4-aminobenzenesulphonamido)-1,3-dihydro-2H-indol-2-one; and

[0185] 6-(4-chlorobenzenesulphonamido)-1,3-dihydro-2H-indol-2-one;

[0186] or a salt pro-drug or solvate thereof.

[0187] According to a further aspect of the eighth feature of theinvention there is provided a compound of Formula (VIII), as definedabove,

[0188] with the proviso that:

[0189] (i) when X is —S(O₂)N(R₅)— linked at the 4 position of theoxindole ring, n is 0, R₂ and R₃ are each independently hydrogen, q is0, and R₅ is hydrogen, then (R₁)_(p) cannot be 4-methyl;

[0190] (ii) when X is —S(O₂)N(R₅)— linked at the 5 position of theoxindole ring, n is 0, R₂ is hydrogen or methyl, R₃ is hydrogen, q is 0and R₅ is hydrogen or methyl, then (R₁)_(p) cannot be 4-methyl;

[0191] (iii) when X is —N(R₅)S(O2)— linked at the 5-position of theoxindole ring, n is 0 or 1, R²and R³ are each independently hydrogen, qis 0 and R⁵ is hydrogen, methyl or ethyl, then p cannot be 0 and(R₁)_(p) cannot be 3-methyl, 2-methoxy, 3-methoxy, 3 chloro, 4-fluoro,or 2-fluoro-4-chloro.

[0192] (iv) when X is —S(O₂)N(R₅)— linked at the 6 position of theoxindole ring, n is 0, R₂ and R₃ are each independently hydrogen, q is 0and R₅ is hydrogen or methyl, then (R₁)_(p) cannot be 4-methyl; and

[0193] (v) when X is —S(O₂)N(R₅)— linked at the 7 position of theoxindole ring, n is 0, R₂ is hydrogen or methyl, R₃ is hydrogen, q is 0and R₅ is hydrogen, then (R₁)_(p) cannot be 4-methyl, 4-methoxy, 4-aminoor 4-chloro;

[0194] or a salt, pro-drug or solvate thereof.

[0195] According to a further aspect of the third, fourth, fifth, sixth,seventh or eight feature of the invention there is provided the use of acompound of Formula (III), Formula (IV), Formula (V), Formula (VI),Formula (VII) or Formula (VIII) respectively, orpharmaceutically-acceptable salt, pro-drug or solvate thereof in themanufacture of a medicament to inhibit and/or reverse and/or alleviatesymptom of angiogenesis and/or any disease state associated withangiogenesis, in a warm blooded animal.

[0196] According to a further aspect of the third, fourth, fifth, sixth,seventh or eight feature of the invention there is provided apharmaceutical composition comprising a compound of Formula (III),Formula (IV), Formula (V), Formula (VI), Formula (VII) or Formula (VIII)respectively, or a pharmaceutically-acceptable salt, pro-drug or solvatethereof, in admixture with a pharmaceutically-acceptable diluent orcarrier for the treatment of a warm-blooded animal, to inhibit and/orreverse and/or alleviate symptom of angiogenesis and/or any diseasestate associated with angiogenesis.

[0197] A preferred group of values of X in each feature of the inventionis —O—, —S—, —S(O)—, —S(O₂)—, or —N(R₅)—. Preferably X is —O—, —S— or—N(R₅)—. Most preferably X is —O— or —S—.

[0198] Preferably when n is 0, X is linked at the 5-position of theindole ring.

[0199] Preferably when n is 1, X is linked at the 6-position of theindole ring.

[0200] A preferred group of values of R₁ in each feature of theinvention is hydrogen, amino, hydroxy, methyl or methoxy wherein theamino group is optionally substituted by an amino acid and the hydroxygroup is optionally esterified. Preferably R₁ is hydrogen, amino,hydroxy, glutaminylamino, serylamino, alanylamino, glycylamino or—PO₃H₂, wherein the hydroxy group is optionally esterified. Morepreferably R₁ is hydrogen, amino, hydroxy, glutaminylamino, serylamino,glycylamino or —PO₃H₂.

[0201] A preferred group of values of R₂ in each feature of theinvention is hydrogen, methyl or ethyl; Preferably R₂ is hydrogen ormethyl.

[0202] A preferred group of values of R₃ in each feature of theinvention is hydrogen, carbamoyl, or C₁₋₄alkylcarbamoyl. Preferably R₃is hydrogen.

[0203] A preferred group of values of R₄ in each feature of theinvention is hydrogen or C₁₋₄alkyl. Preferably hydrogen.

[0204] A preferred group of compound of each feature of the inventiondescribed herein; comprise compounds wherein:

[0205] X is —O—.

[0206] A further preferred group of compound of each feature of theinvention described herein; comprise compounds wherein:

[0207] X is —N—.

[0208] A further preferred group of compound of each feature of theinvention described herein; comprise compounds wherein:

[0209] X is —S—, —S(O)— or —S(O₂)—, preferably —S—.

[0210] A further preferred group of compound of each feature of theinvention described herein; comprise compounds wherein:

[0211] R₁ is amino, hydroxy or —OPO₃H₂, wherein the amino group isoptionally substituted by an amino acid residue and the hydroxy group isoptionally esterified.

[0212] A further preferred group of compound of each feature of theinvention described herein; comprise compounds wherein:

[0213] R₁ is amino, hydroxy or —OPO₃H₂, wherein the amino group isoptionally substituted by an amino acid residue and the hydroxy group isoptionally esterified; and

[0214] R₃ is carbamoyl, or C₁₋₄alkylcarbamoyl.

[0215] Particular compounds of each feature of the invention are:

[0216] 5-(phenylsulfanyl)-1,3-dihydro-2H-indol-2-one;

[0217] 5-(4-aminophenoxy)-1,3-dihydro-2H-indol-2-one;

[0218] 5-(4-aminophenylsulfanyl)-1,3-dihydro-2H-indol-2-one;

[0219] 5-(4-hydroxyphenylsulfanyl)-1,3-dihydro-2H-indol-2-one; and

[0220] 6-(3-aminobenzyloxy)-1,3-dihydro-2H-indol-2-one;

[0221] or a salt, pro-drug or solvate thereof

[0222] More particular compounds of each feature of the invention are:

[0223] 5-(4-N-glutaminylaminophenoxy)-1,3-dihydro-2H-indol-2-one;

[0224] 5-(4-N-Serylaminophenoxy)-1,3-dihydro-2H-indol-2-one;

[0225] 5-(4-N-Glycylaminophenoxy)-1,3-dihydro-2H-indol-2-one;

[0226] 5-(4-N-glutaminylaminophenylsulfanyl-1,3-dihydro-2H-indol-2-one;

[0227] 5-(3-N-glutaminylaminobenzyloxy)-1,3-dihydro-2H-indol-2-one; and

[0228] 5-(4-phosphonophenylsulfanyl)-1,3-dihydro-2H-indol-2-one

[0229] or a salt, pro-drug or solvate thereof.

[0230] A compound of the invention or a pharmaceutically-acceptablesalt, or solvate thereof, may be prepared by any process known to beapplicable to the preparation of chemically related compounds. Suchprocesses, when used to prepare a compound of the invention or apharmaceutically-acceptable salt, or solvate thereof, are provided as afurther feature of the invention and are illustrated by the followingrepresentative examples in which R₁, R₂, R₃, R₄, R₅, X, n, p and q havethe same meaning as herein before defined. The reader is referred toAdvanced Organic Chemistry, 4^(th) Edition, by Jerry March, published byJohn Wiley & Sons 1992, for general guidance on reaction conditions andreagents. The reader is referred to Protective Groups in OrganicSynthesis 2^(nd) Edition, by Green et al, published by John Wiley & Sonsfor general guidance on protecting groups.

[0231] Thus, according to the ninth feature of the invention there isprovided a process for preparing a compound of Formula (I), or salt,pro-drug or solvate thereof, which process (wherein n, p, q, X, R₁, R₂,R₃, R₄ and R₅ are unless otherwise specified as defined in Formula (I))comprises:

[0232] a) for compounds of Formula (I) wherein X is —O—, —S— or —N(R₅)—,reacting a compound of Formula (A) with a compound of Formula (B),

[0233] wherein L₁ is a leaving group;

[0234] b) for compounds of Formula (I) wherein R₂ is hydrogen, reductionof a compound of Formula (C), wherein R₆ is hydrogen or an alkyl chain,

[0235] c) for compounds of Formula (I) wherein R₂ is C₁₋₄alkyl, reactinga compound of Formula (I) wherein R₂ is hydrogen with a suitablealkylhalide;

[0236] d) for compounds of Formula (I) wherein R₂ is hydrogen and R₃ ishydrogen reacting a compound of Formula (D) with an alkylthioacetate,followed by reduction,

[0237] e) for compounds of Formula (I) wherein X is —S(O₂)N(R₅)—,reacting a compound of Formula (E) with an amine of Formula (F),

[0238] wherein L₃ is a displaceable group;

[0239] f) for compounds of Formula (I) wherein X is —N(R₅)S(O₂)—;reacting an amine of Formula (G) with a compound of Formula (H),

[0240] wherein L₃ is a displaceable group;

[0241] g) for compounds of Formula (I) wherein X is —S(O)—, —S(O₂)—,oxidising a compound of Formula (J),

[0242] and thereafter if necessary:

[0243] i) converting a compound of the Formula (I) into another compoundof the Formula (I);

[0244] ii) removing any protecting groups;

[0245] iii) forming a salt, pro-drug or solvate.

[0246] According to a further aspect of the ninth feature of theinvention there is provided the processes a), b), c), d), e), f), and g)described above for the preparation of compounds of the Formula (II),Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII) orFormula (VIII), or a salt, pro-drug or solvate thereof,.

[0247] Specific reaction conditions for the above reactions are asfollows:

[0248] Process a) Compounds of Formula (A) and compound of Formula (B)can be reacted together in an organic solvent, at a temperature betweenroom temperature and about 80° C., optionally in the presence of a basesuch as sodium hydride, potassium carbonate or triethylamine.

[0249] Process b) The conditions for reduction of a compound of Formula(C) are well known in the art. Examples of reducing agents includehydrogen and a hydrogenation catalyst (for example palladium on carbon),iron and acetic acid, and zinc and hydrochloric acid. The reaction ispreferable carried out in the presence of a suitable solvent such as analcohol, for example methanol or ethanol, and at a temperature in therange of 0-80° C., preferably at or near room temperature.

[0250] Process c) Compounds of Formula (I) wherein R₂ is hydrogen and asuitable alkylhaldie may be reacted together in a suitable organicsolvent such as DMF or DMSO, in the presence of a base, such as sodiumhydride or potassium carbonate at a temperature between about roomtemperature and about 80° C.

[0251] Process d) Compounds of Formula (D) can be reacted with aalkylthioacetate in the presence of SO₂Cl₂ and in the presence of abases such as triethylamine, followed by reduction with a suitablereducing agent, such as Raney Nickel in a suitable polar solvent, suchas ethanol or methanol at approximately room temperature.

[0252] Process e) and f) The reaction of compounds of Formula (E) andFormula (F) or the reaction of Formula (G) and Formula (H) where L₃ is adisplaceable group is well known in the art, for example they may bereacted in the presence of a base, for example triethylamine, pyridine,or 2,6-di-alkyl-pyridines such as 2,6-lutidine or2,6-di-tert-butylpyridine, and in a suitable solvent, such as DMA, DCM,benzene, THF and DMF. The reaction may conveniently be performed at atemperature in the range of −40 to 140° C.

[0253] Process g) The oxidization of a compound of Formula (J) is wellknown in the art, for example, reaction with metachloroperbenzoic acid(MCPBA) is the presence of a suitable solvent such as dichloromethane atambient temperature. If an excess of MCPBA is used a S compound ofFormula (I) wherein X is —S(O₂)— is obtained.

[0254] Intermediates for the processes a), b), c) and d) can be preparedas outlined in Scheme 1, wherein P is protecting group, using thefollowing reaction conditions:

[0255] Reaction Conditions (i) Reaction with chloroacetate in an organicsolvent such as DMF or acetone, in the presence of a base such as sodiumhydride or potassium carbonate at a temperature between approximatelyroom temperature and approximately 80° C.

[0256] Reaction Conditions (ii) Reduction using a suitable reducingagent such as hydrogen and a hydrogenation catalyst (for examplepalladium on carbon), iron and acetic acid, or zinc and hydrochloricacid.

[0257] Reaction Conditions (iii) Reaction conditions for the removal ofa protecting group are well know in the art.

[0258] The compounds used as starting points for the reactions describedabove are commercially available or they are known compounds or they areprepared by processes know in the art.

[0259] It will also be appreciated that in some of the reactionsmentioned herein it may be necessary/desirable to protect any sensitivegroups in the compounds. The instances where protection is necessary ordesirable and suitable methods for protection are known to those skilledin the art. Conventional protecting groups may be used in accordancewith standard practice (for illustration see T. W. Green, ProtectiveGroups in Organic Synthesis, John Wiley and Sons, 1991). Thus, ifreactants include groups such as amino, carboxy or hydroxy it may bedesirable to protect the group in some of the reactions mentionedherein.

[0260] A suitable protecting group for an amino or alkylamino group is,for example, an acyl group, for example an alkanoyl group such asacetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group,for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.The deprotection conditions for the above protecting groups necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or alkoxycarbonyl group or an aroyl group maybe removed for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

[0261] A suitable protecting group for a hydroxy group is, for example,an acyl group, for example an alkanoyl group such as acetyl, an aroylgroup, for example benzoyl, or an arylmethyl group, for example benzyl.The deprotection conditions for the above protecting groups willnecessarily vary with the choice of protecting group. Thus, for example,an acyl group such as an alkanoyl or an aroyl group may be removed, forexample, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

[0262] A suitable protecting group for a carboxy group is, for example,an esterifying group, for example a methyl or an ethyl group which maybe removed, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

[0263] The protecting groups may be removed at any convenient stage inthe synthesis using conventional techniques well known in the chemicalart.

[0264] In order to use a compound of the Formula (I) or Formula (II) orFormula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII) orFormula (VIII) or a pharmaceutically-acceptable salt or in vivocleavable ester thereof, for the therapeutic treatment (includingprophylactic treatment) of mammals including humans, it is normallyformulated in accordance with standard pharmaceutical practice as apharmaceutical composition.

[0265] The compositions of the invention may be in a form suitable fororal use (for example as tablets, lozenges, hard or soft capsules,aqueous or oily suspensions, emulsions, dispersible powders or granules,syrups or elixirs), for topical use (for example as creams, ointments,gels, or aqueous or oily solutions or suspensions), for administrationby inhalation (for example as a finely divided powder or a liquidaerosol), for administration by insufflation (for example as a finelydivided powder) or for parenteral administration (for example as asterile aqueous or oily solution for intravenous, subcutaneous,intramuscular or intramuscular dosing or as a suppository for rectaldosing).

[0266] The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

[0267] Suitable pharmaceutically-acceptable excipients for a tabletformulation include, for example, inert diluents such as lactose, sodiumcarbonate, calcium phosphate or calcium carbonate, granulating anddisintegrating agents such as corn starch or algenic acid; bindingagents such as starch; lubricating agents such as magnesium stearate,stearic acid or talc; preservative agents such as ethyl or propylp-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tabletformulations may be uncoated or coated either to modify theirdisintegration and the subsequent absorption of the active ingredientwithin the gastrointestinal tract, or to improve their stability and/orappearance, in either case, using conventional coating agents andprocedures well known in the art.

[0268] Compositions for oral use may be in the form of hard gelatincapsules in which the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules in which the active ingredient is mixed withwater or an oil such as peanut oil, liquid paraffin, or olive oil.

[0269] Aqueous suspensions generally contain the active ingredient infinely powdered form together with one or more suspending agents, suchas sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

[0270] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil (such as arachis oil, olive oil, sesameoil or coconut oil) or in a mineral oil (such as liquid paraffin). Theoily suspensions may also contain a thickening agent such as beeswax,hard paraffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

[0271] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

[0272] The pharmaceutical compositions of the invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, such as olive oil or arachis oil, or a mineral oil, such as forexample liquid paraffin or a mixture of any of these. Suitableemulsifying agents may be, for example, naturally-occurring gums such asgum acacia or gum tragacanth, naturally-occurring phosphatides such assoya bean, lecithin, an esters or partial esters derived from fattyacids and hexitol anhydrides (for example sorbitan monooleate) andcondensation products of the said partial esters with ethylene oxidesuch as polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening, flavouring and preservative agents.

[0273] Syrups and elixirs may be formulated with sweetening agents suchas glycerol, propylene glycol, sorbitol, aspartame or sucrose, and mayalso contain a demulcent, preservative, flavouring and/or colouringagent.

[0274] The pharmaceutical compositions may also be in the form of asterile injectable aqueous or oily suspension, which may be formulatedaccording to known procedures using one or more of the appropriatedispersing or wetting agents and suspending agents, which have beenmentioned above. A sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example a solution in 1,3-butanediol.

[0275] Suppository formulations may be prepared by mixing the activeingredient with a suitable non-irritating excipient which is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Suitable excipientsinclude, for example, cocoa butter and polyethylene glycols.

[0276] Topical formulations, such as creams, ointments, gels and aqueousor oily solutions or suspensions, may generally be obtained byformulating an active ingredient with a conventional, topicallyacceptable, vehicle or diluent using conventional procedures well knownin the art.

[0277] Compositions for administration by insufflation may be in theform of a finely divided powder containing particles of average diameterof, for example, 30 μm or much less, the powder itself comprising eitheractive ingredient alone or diluted with one or more physiologicallyacceptable carriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

[0278] Compositions for administration by inhalation may be in the formof a conventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

[0279] For further information on formulation the reader is referred toChapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (CorwinHansch; Chairman of Editorial Board), Pergamon Press 1990.

[0280] The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

[0281] The size of the dose for therapeutic or prophylactic purposes ofa compound of the Formula (I), Formula (II) or Formula (III), Formula(IV), Formula (V), Formula (VI), Formula (VII) or Formula (VIII) willnaturally vary according to the nature and severity of the conditions,the age and sex of the animal or patient and the route ofadministration, according to well known principles of medicine.

[0282] In using a compound of the Formula (I), Formula (II), Formula(III), Formula (IV), Formula (V), Formula (VI), Formula (VII) or Formula(VIII) for therapeutic or prophylactic purposes it will generally beadministered so that a daily dose in the range, for example, 0.5 mg to75 mg per kg body weight is received, given if required in divideddoses. In general lower doses will be administered when a parenteralroute is employed. Thus, for example, for intravenous administration, adose in the range, for example, 0.5 mg to 20 mg per kg body weight willgenerally be used. Intranvenous administration is however preferred,typically, intravenous doses of about 10 mg to 500 mg per patient of acompound of this invention.

[0283] The compounds of this invention may be used in combination withother drugs and therapies used to inhibit and/or reverse and/oralleviate symptom of angiogenesis and/or any disease state associatedwith angiogenesis. Examples of such disease states include: cancer,diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma,haemangioma, acute and chronic nephropathies, atheroma, arterialrestenosis, autoimmune diseases, acute inflammation, endometriosis,dysfunctional uterine bleeding and ocular diseases with retinal vesselproliferation.

[0284] If formulated as a fixed dose such combination products employthe compounds of this invention within the dosage range described hereinand the other pharmaceutically-active agent within its approved dosagerange. Sequential use is contemplated when a combination formulation isinappropriate.

[0285] According to the tenth feature of the present invention there isprovided a compound of Formula (I), Formula (II), Formula (III), Formula(IV), Formula (V), Formula (VI), formula (VII) or Formula (VIII), orsalt, pro-drug or solvate thereof, preferably in the form of apharmaceutical composition, when dosed in divided doses (also known assplit doses) produces a greater anti-tumour effect than when a singledose is given.

[0286] Anti-tumour effects include but are not limited to, inhibition oftumour growth, tumour growth delay, regression of tumour, shrinkage oftumour, increased time to re-growth of tumour on cessation of treatment,slowing of disease progression. It is expected that when a method oftreatment of the present invention is administered to a warm-bloodedanimal such as a human, in need of treatment for cancer involving asolid tumour, said method of treatment will produce an effect, asmeasured by, for example, one or more of: the extent of the anti-tumoureffect, the response rate, the time to disease progression and thesurvival rate.

[0287] According to a further aspect of the tenth feature of the presentinvention there is provided a method for the production of a vasculardamaging effect in a warm-blooded animal such as a human, whichcomprises administering to said animal in divided doses an effectiveamount of a compound of Formula (I), Formula (II), Formula (III),Formula (IV), Formula (V), Formula (VI), Formula (VII) or Formula(VIII), or salt, pro-drug or solvate thereof, preferably in the form ofa pharmaceutical composition.

[0288] According to a further aspect of the tenth feature of the presentinvention there is provided a method for the treatment of a cancerinvolving a solid tumour in a warm-blooded animal such as a human, whichcomprises administering to said animal in divided doses an effectiveamount of a compound of Formula (I), Formula (II), Formula (III),Formula (IV), Formula (V), Formula (VI), Formula (VII) or Formula(VIII), or salt, pro-drug or solvate thereof, preferably in the form ofa pharmaceutical composition.

[0289] According to a further aspect of the tenth feature of the presentinvention there is provided a medicament comprising two or morefractions of doses of a compound of Formula (I), Formula (II), Formula(III), Formula (IV), Formula (V), Formula (VI), Formula (VII) or Formula(VIII), or salt, pro-drug or solvate thereof , preferably in the form ofa pharmaceutical composition, which together add up to a total dailydose, for administration in divided doses for use in a method oftreatment of a human or animal body by therapy.

[0290] According to a further aspect of the tenth feature of the presentinvention there is provided a kit comprising two or more fractions ofdoses of a compound of Formula (I), Formula (II), Formula (III), Formula(IV), Formula (V), Formula (VI), Formula (VII) or Formula (VIII), orsalt, pro-drug or solvate thereof, preferably in the form of apharmaceutical composition, which together add up to a total daily dose,for administration in divided doses.

[0291] According to a further aspect of the tenth feature of the presentinvention there is provided a kit comprising:

[0292] a) two or more fractions of doses of a compound of Formula (I),Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI),Formula (VII) or Formula (VIII), or salt, pro-rug or solvate thereof, ,which together add up to a total daily dose, in unit dosage forms foradministration in divided doses;

[0293] b) container means for containing said dosage forms.

[0294] According to a further aspect of the tenth feature of the presentinvention there is provided a kit comprising:

[0295] a) two or more fractions of doses of a compound of Formula (I),Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI),Formula (VII) or Formula (VIII), or salt, pro-drug or solvate thereof,which together add up to a total daily dose, together with a excipientor carrier, in unit dosage forms; and

[0296] b) container means for containing said dosage forms.

[0297] According to a further aspect of the tenth feature of the presentinvention there is provided the use of a compound of Formula (I),Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI),Formula (VII) or Formula (VIII), or salt, pro-drug or solvate thereof,in the manufacture of a medicament for administration in divided dosesfor use in the production of a vascular damaging effect in awarm-blooded animal such as a human.

[0298] According to a further aspect of the tenth feature of the presentinvention there is provided the use of a compound of Formula (I),Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI),Formula (VII) or Formula (VIII), or salt, pro-drug or solvate thereof,in the manufacture of a medicament for administration in divided dosesfor use in the production of an anti-cancer effect in a warm-bloodedanimal such as a human.

[0299] According to a further aspect of the tenth feature of the presentinvention there is provided the use of a compound of Formula (I),Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI),Formula (VII) or Formula (VIII), or salt, pro-drug or solvate thereof,in the manufacture of a medicament for administration in divided dosesfor use in the production of an anti-tumour effect in a warm-bloodedanimal such as a human.

[0300] Divided doses, also called split doses, means that the total doseto be administered to a warm-blooded animal, such as a human, in any oneday period (for example one 24 hour period from midnight to midnight) isdivided up into two or more fractions of the total dose and thesefractions are administered with a time period between each fraction ofabout greater than 0 hours to about 10 hours, preferably about 1 hour toabout 6 hours, more preferably about 2 hours to about 4 hours. Thefractions of total dose may be about equal or unequal.

[0301] Preferably the total dose is divided into two parts which may beabout equal or unequal.

[0302] The time intervals between doses may be for example selectedfrom: about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours,about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5hours, about 5.5 hours and about 6 hours.

[0303] The time intervals between doses may be any number (includingnon-integers) of minutes between greater than 0 minutes and 600 minutes,preferably between 45 and 375 minutes inclusive. If more than two dosesare administered the time intervals between each dose may be about equalor unequal.

[0304] Preferably two doses are given with a time interval in betweenthem of greater than or equal to 1 hour and less than 6 hours.

[0305] More preferably two doses are given with a time interval inbetween them of greater than or equal to two hours and less than 5hours.

[0306] Yet more preferably two doses are given with a time interval inbetween them of greater than or equal to two hours and less than orequal to 4 hours.

[0307] Particularly the total dose is divided into two parts which maybe about equal or unequal with a time interval between doses of greaterthan or equal to about two hours and less than or equal to about 4hours.

[0308] More particularly the total dose is divided into two parts whichmay be about equal with a time interval between doses of greater than orequal to about two hours and less than or equal to about 4 hours.

[0309] For the avoidance of doubt the term ‘about’ in the description oftime periods means the time given plus or minus 15 minutes, thus forexample about 1 hour means 45 to 75 minutes, about 1.5 hours means 75 to105 minutes. Elsewhere the term ‘about’ has its usual dictionarymeaning.

[0310] Although the compounds of the Formula (I), Formula (II), Formula(III), Formula (IV), Formula (V), Formula (VI), Formula (VII) or Formula(VIII) are primarily of value as therapeutic agents for use inwarm-blooded animals (including man), they are also useful whenever itis required to inhibit and/or reverse and/or alleviate symptom ofangiogenesis and/or any disease state associated with angiogenesis.Thus, they are useful as pharmacological tools for use in thedevelopment of new biological tests and in the search for newpharmacological agents.

[0311] Biological Assay

[0312] Colchicine Binding Site Competitive Assay Kit.

[0313] The ability of a ligand to bind specifically to the colchicinebinding site on tubulin, an indicator of the vascular damaging activity,was assessed using a size exclusion chromatography assay kit from“Cytoskeleton” (1650 Fillmore St. #240, Denver, Colo. 80206, U.S.A.)Catalogue number of kit: BK023.

[0314] The following reagents were used:

[0315] tubulin buffer, to give 0.1 mM GTP, 0.5 mM MgCl₂, 0.5 mM EGTA, 40mM PIPES buffer at pH6.9 in the final reaction mix;

[0316] purified tubulin protein from bovine brain at 1 mg/ml in tubulinbuffer;

[0317] 0.02 mM fluorescent colchicine in tubulin buffer [FITC(fluorescein isothiocyanate)-labelled];

[0318] 2 mM colchicine in tubulin buffer;

[0319] 0.2 mM vinblastine in tubulin buffer; and

[0320] G-25 Sephadex™ Fine—particle size 34-138 μm.

[0321] The reaction was performed as follows: 8 μl of test compound(dissolved in DMSO) was gently mixed with 150 μl of tubulin. This wasthen incubated at 37° C. for 30 minutes. Then 4 μl of the fluorescentcolchicine was added, the incubation mix vortexed for 5 seconds and thenincubated for a further 30 minutes at 37° C. At the end of the reactionincubation size exclusion chromatography was performed to separate thetubulin with fluorescent colchicine bound from the free, unboundcolchicine. If a test compound inhibited fluorescent colchicine bindingthen a reduced signal is measured and the compound is confirmed as acolchicine site binding moiety.

[0322] Chromatography was performed as follows, using chromatographycolumns filled with 3 mls of G-25 Sephadex™ Fine slurry. The incubationmixture was pipetted onto the column and up to 12 elutions of 160 μlwere collected. The fluorescence of the tubulin-containing fractions wasdetected on a spectrophotometer which excites at 485 nm and emits at 535nm. Control incubations were also performed, 8 μl DMSO (negativecontrol) and 8 μl colchicine stock (positive competition control),instead of the 8 μl of test compound in the incubation mixture.

[0323] The degree of competition of colchicine binding by eitherunlabelled colchicine or test compound was calculated relative to theDMSO negative control.

[0324] Compounds of Formula (I) encompass vascular damaging agents andpro-drugs of vascular damaging agents. Pro-drugs of vascular damagingagents are believed to be cleaved in-vivo. Without being bound bytheoretical considerations these pro-drugs may have lower activity inthe in-vitro colchicine binding site competitive assay, than would beanticipated when the activity of these compounds is measured in cellbased assays or in-vivo.

[0325] The invention will now be illustrated in the followingnon-limiting Examples in which, unless otherwise stated:

[0326] (i) evaporations were carried out by rotary evaporation in vacuoand work-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

[0327] (ii) operations were carried out at ambient temperature, that isin the range 18-25° C. and under an atmosphere of an inert gas such asargon or nitrogen;

[0328] (iii) yields are given for illustration only and are notnecessarily the maximum attainable;

[0329] (iv) the structures of the end-products of the Formula I wereconfirmed by nuclear (generally proton) magnetic resonance (NMR) andmass spectral techniques; proton magnetic resonance chemical shiftvalues were measured on the delta scale and peak multiplicities areshown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br,broad; q, quartet, quin, quintet;

[0330] (v) intermediates were not generally fully characterised andpurity was assessed by thin layer chromatography (TLC), high-performanceliquid chromatography (HPLC), infra-red (IR) or NMR analysis;

[0331] (vi) flash chromatography was performed on silica (MerckKeiselgel: Art.9385);

[0332] (vii) OASIS™ is a macroporous co-polymer, used to purifyhydrophilic compounds, made form a balanced ratio of lipophilrcdivinylbenzene and hydrophillic N-vinylpyrrolidone. OASIS™ is describedin the following patents, U.S. Pat. No. 5,882,521, U.S. Pat. No.5,976,376 and U.S. Pat. No. 6,106,721. OASIS™ sample extraction productswere obtained from Waters Corporation (Milford, Mass., USA).

[0333] (viii) HP20SS resin (DIAION® HP20SS) was obtained from MitsubishiChemical America Inc.

[0334] Abbreviations

[0335] 4-Dimethylaminopyridine DMAP

[0336] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI

[0337] Dimethyl sulphoxide DMSO

[0338] Trifluoroacetic acid TFA

[0339] N-(9-fluorenylmethoxycarbonyl) N-FMOC

[0340] N-tert-Butoxycarbonyl N-Boc

[0341] Potassium tert-butylate tBuOK

EXAMPLE 1 5-(phenylsulfanyl)-1,3-dihydro-2H-indol-2-one

[0342]

[0343] A suspension of 3 (1.52 g; 5.2 mmol) and zinc (1.38 g; 21 mmol)in 50% H₂SO₄ (20 ml) and ethanol (30 ml) was heated at 100° C. for 10hours. After evaporation of ethanol, the mixture was extracted withAcOEt and purified by flash chromatography eluting with CH₂Cl₂/EtOH 96/4to give 5-(phenylsulfanyl)-1,3-dihydro-2H-indol-2-one.

[0344] Yield: 31%.

[0345]¹HNMR (CDCl₃): 3.52 (s, 2H); 6.84 (d, 1H); 7.1-7.4 (m, 7H); 8.04(s, 1H).

[0346] MS-ESI: 240 [M−H]⁻.

[0347] The starting material was prepared as follows:

[0348] A suspension of t-BuOK (6.73 g; 60 mmol) in THF (70 ml) wascooled to −40° C. under argon and treated with a solution of 1 (5.78 g;25 mmol) and ethyl chloroacetate (3.7 g; 30 mmol) in THF (30 ml). Themixture was stirred at −40° C. for 2 hours. HCl (2N; 40 ml) was addedand the mixture was stirred at ambient temperature for 15 minutes andextracted with AcOEt/H₂O. The organic phase was evaporated and purifiedby flash chromatography eluting with petroleum ether/AcOEt 90/10 to give2.

[0349] Yield: 33%.

[0350]¹H NMR spectrum (CDCl₃): 1.24 (t, 3H); 3.92 (s, 2H); 4.15 (q, 2H);7.03 (d, 1H); 7.08 (dd, 1H); 7.43-7.48 (m, 3H); 7.52-7.56 (m, 2H); 8.01(d, 1H).

[0351] MS-ESI:316 [M−H]⁻.

[0352] A solution of 2 (2.61 g; 8.2 mmol) in dioxan (25 ml) was treatedwith NaOH (2N, 5.4 ml) at ambient temperature for 5 hours. The solutionwas acidified to pH 2 with 6N HCl and extracted with AcOEt and purifiedby flash chromatography, eluting with CH₂Cl₂/EtOH 96/4 to give 3.

[0353] Yield: 64%.

[0354]¹H NMR spectrum (CDCl₃): 3.96 (s, 2H); 1.01 (d, 1H); 7.09 (dd,1H); 7.43-7.49 (m, 3H); 7.52-7.58 (m, 2H); 8.03 (d, 1H).

EXAMPLE 2 5-(4-aminophenoxy)-1,3-dihydro-2H-indol-2-one

[0355]

[0356] Fe (0.387 g; 6.9 mmol) was added to a solution of 5 (0.4 g; 1.1mmol) in AcOH (10 ml). The mixture was heated at 80° C. for 30 minutesand evaporated to dryness. The residue was taken up in water. Thesolution was adjusted to pH 7.5 with sat. NaHCO₃ and extracted withAcOEt. The residue was purified by flash chromatography eluting withCH₂Cl₂/MeOH 97/3 to give 5-(4-aminophenoxy)-1,3-dihydro-2H-indol-2-one.

[0357] Yield: 41%.

[0358]¹H NMR spectrum (CDCl₃): 3.43 (s, 2H); 4.89 (s, 2H); 6.55 (d, 2H);6.66-6.76 (m, 4H); 6.78 (d, 1H); 10.24 (s, 1H).

[0359] MS-ESI: 241 [M+H]⁺.

[0360] The starting material 5 was prepared from 4 as described inexample 1.

[0361] Yield: 28%.

[0362]¹HNMR spectrum (CDCl₃): 1.27 (t, 3H); 4.01 (s, 2); 4.19 (q, 21H);7.01 (d, 1H); 7.09 (dd, 1H); 7.18 (d, 2H); 8.22 (d, 1H); 8.30 (d, 2H).)

EXAMPLE 3 5-(4-aminophenylsulfanyl)-1,3-dihydro-29-indol-2-one

[0363]

[0364] was prepared as described for example 2 but using 7 inreplacement of 5.

[0365] Yield: 14%.

[0366]¹H NMR spectrum (CDCl₃): 3.47 (s, 2H); 3.77 (s, 2H); 6.62 (d, 2H);6.74 (d, 1H); 7.10 (s, 1H); 7.14 (d, 1H); 7.25 (d, 2H); 7.70 (d, 1H).

[0367] MS-ESI: 255 [M−H]⁻.

[0368] The starting material 7 was prepared as described in example 2for 5 starting from 6.

[0369]¹H NMR spectrum (CDCl₃): 1.27 (t, 3H); 3.98 (s, 2H); 4.18 (q, 2H);7.3-7.7 (4H); 8-8.3 (m, 3H).

EXAMPLE 4 5-(4-N-glutaminylaminophenoxy)-1,3-dihydro-2H-indol-2-one

[0370]

[0371] A solution of 10 (0.2 g; 0.47 mmol) in solution in CH₂Cl₂ (1 ml)was treated with a solution of HCl (20%) in dioxan (2.5 ml). Afterstirring at ambient temperature for 2 hours the mixture was evaporatedand purified on HP20SS resin, eluting with water to give5-(4-N-glutaminylaminophenoxy)-1,3-dihydro-2H-indol-2-one.

[0372] Yield: 81%.

[0373]¹H NMR spectrum (DMSOd₆): 2.01-2.13 (m, 2H); 2.39 (t, 2H); 3.47(s, 2H); 3.93-4.05 (m, 1H); 6.80 (d, 1H); 6.85 (dd, 1H); 6.93 (d, 1H);6.96 (d, 2H); 7.58 (d, 2H); 8.34 (bs, 2H); 10.37 (s, 1H); 10.55 (s, 1H);12.35 (bs, 1H).

[0374] MS-ESI: 368 [M−H]⁻. Elemental analysis Found C 53.21 H 5.05 N9.93 Cl 7.96 C₁₉H₁₉N₃O₅, Requires C 54.28 H 5.22 N 9.99 Cl 8.01 0.91H₂O, 0.95 HCl

[0375] The starting material was prepared as follows:

[0376] A solution of 5-(4-aminophenoxy)-1,3-dihydro-2H-indol-2-one(Example 2) (0.24 g; 1 mmol), 8 (0.638 g; 1.5 mmol), EDCI (0.288 g; 1.5mmol) and DMAP (0.005 g; 0.02 mmol) in CH₂Cl₂ (7 ml) was stirred underargon for 2 hours. The mixture was purified by flash chromatographyeluting with CH₂Cl₂/MeOH 98/2 to give 9 which was redissolved in CHCl₃(3.5 ml) and treated with piperidine (1 ml). After stirring for 1 h 30,the mixture was diluted with water and extracted with CH₂Cl₂. Theorganic phase was purified by flash chromatography eluting withCH₂Cl₂/MeOH 95/5 to give 10.

[0377] Yield: 47%/.

[0378]¹H NMR spectrum (DMSOd6): 1.39 (s, 9H); 1.59-1.72 (m, 1H);1.80-1.92 (m, 1H); 2.21-2.39 (m, 2H); 3.25-3.33 (m, 2H); 3.46 (s, 2H);6.79 (d, 1H); 6.83 (dd, 1H); 6.89-6.93 (m, 3H); 7.60 (d, 2H); 9.85 (bs,1H); 10.33 (s, 1H).

[0379] MS-ESI: 424 [M−H]⁻.

EXAMPLE 5 5-(4-N-Serylaminophenoxy)-1,3-dihydro-2H-indol-2-one

[0380]

[0381] A solution of 12 (0.21 g; 0.49 mmol) in CH₂Cl₂ (2 ml) was treatedwith a solution of HCl/dioxan (2,4 N; 2 ml). After stirring at ambienttemperature for 2 h 30, the mixture was evaporated to dryness. Theresidue was taken up in water, DMF and purified on HP20SS resin afterneutralisation to pH 7.5 with 0.5 N NaOH. After elution with CH₃CN/H₂O50/50, the appropriate fractions were acidified to pH 3 and freeze driedto give 5-(4-N-Serylaminophenoxy)-1,3-dihydro-2H-indol-2-one.

[0382] Yield: 64%.

[0383]¹H NMR spectrum (DMSOd₆): 3.47 (s, 2H); 3.81-3.87 (m, 2H); 3.99(bs, 1H); 5.56 (bs, 1H); 6.80 (d, 1H); 6.84 (dd, 1H); 6.92 (s, 1H); 6.95(d, 2H); 7.60 (d, 2H); 8.27 (bs, 2H); 10.36 (s, 1H); 10.61 (s, 1H).

[0384] MS-ESI: 328 [M+H]⁺.

[0385] The starting material was prepared as follows:

[0386] A solution of 5-(4-aminophenoxy)-1,3dihydro-2H-indol-2-one(Example 2) (0.24 g; 1 mmol), 11 (0.267 g; 1 mmol), EDCI (0.346 g; 1.8mmol) and DMAP (0.020 g; 0.16 mmol) in CH₂Cl₂ (5 ml) was stirred underargon overnight. The mixture was purified by flash chromatographyeluting with CH₂Cl₂/MeOH 97/3 to give 12.

[0387] Yield: 50%.

[0388]¹H NMR spectrum (DMSOd₆): 1.38 (s, 9H); 3.46 (s, 2H); 3.5 (bs,2H); 4.07-4.18 (m, 1H); 4.92 (t, 1H); 6.73 (d, 1H); 6.78 (d, 1H); 6.82(d, 1H); 6.88-6.95 (m, 3H); 7.58 (d, 2H); 9.91 (s, 1H); 10.32 (s, 1H).

EXAMPLE 6 5-(4-N-Glycylaminophenoxy)-1,3-dihydro-2H-indol-2-one

[0389]

[0390] A solution of 14 (0.681 g; 1.71 mmol) in CH₂Cl₂ (2 ml) wastreated with a solution of HCl/dioxan (2.4 N; 6 ml). The mixture wasstirred at ambient temperature for 1 hour and evaporated. The residuewas taken up in DMF/H₂O, neutralised to pH 7 with 2N NaOH and purifiedon reverse phase silica eluting with a gradient of CH₃CN/H₂O. Theappropriate fractions were acidified to pH 3.2 with 2N HCl and freezerdried to give 5-(4-N-Glycylaminophenoxy)-1,3-dihydro-2H-indol-2-one.

[0391] Yield: 43%.

[0392]¹H NMR spectrum (DMSOd6): 3.47 (s, 2H); 3.75 (s, 2H); 6.80 (d,1H); 6.85 (dd, 1H); 6.93 (d, 1H); 6.95 (d, 2H); 7.57 (d, 2H); 8.15 (bs,2H); 10.36 (s, 1H); 10.58 (s, 1H).

[0393] MS-ESI: 298 [M+H]⁺.

[0394] The starting material was prepared as described for compound 12but using 13 in replacement of 11.

[0395] Yield: 85%.

[0396]¹H NMR spectrum (DMSOd6):1.39 (s, 9H); 3.47 (s, 2H); 3.59 (d, 2H);6.78 (d, 1H); 6.83 (dd, 1H); 6.89-6.95 (m, 3H); 7.03 (t, 1H); 7.54 (d,2H); 9.88 (s, 1H); 10.32 (s, 1H).

EXAMPLE 75-(4-N-glutaminylaminophenylsulfanyl-1,3-dihydro-2H-indol-2-one

[0397]

[0398] The compound was prepared as described in example 4 (replacing 10by 18).

[0399] Yield: 70%.

[0400]¹H NMR spectrum (DMSOd6): 1.98-2.15 (m, 2H); 2.38 (t, 2H); 3.48(s, 2H); 3.94-4.08 (m, 1H); 6.85 (d, 1H); 7.20-7.31 (m, 4H); 7.58 (d,2H); 8.36 (bs, 2H); 10.54 (s, 1H); 10.80 (s, 1H); 12.30 (bs, 1H).

[0401] MS-ESI: 384 [M−H]⁻. Elemental analysis Found C 51.31 H 4.88 N9.35 S 6.99 Cl 6.84 C₁₉H₁₉N₃O₄S, 1.33 H₂O 0.9 HCl Requires C 51.61 H5.14 N 9.50 S 7.25 Cl 7.22

[0402] The starting material was prepared as described in example 4starting from example 3.

[0403] Yield: 44%.

[0404]¹H NMR spectrum (DMSOd6): 1.38 (s, 9H); 1.58-1.69 (m, 1H);1.74-1.91 (m, 1H); 2.23-2.36 (m, 2H); 3.47 (s, 2H); 6.82 (d, 2H);7.18-7.27 (m, 4H); 7.61 (d, 2H); 10.50 (s, 1H).

EXAMPLE 8 5-(4-hydroxyphenylsulfanyl)-1,3-dihydro-2H-indol-2one

[0405]

[0406] 5-(4-hydroxyphenylsulfanyl)-1,3-dihydro-2H-indol-2-one wasprepared as described in example 1.

[0407] Yield: 30%.

[0408]¹H NMR spectrum (DMSOd₆): 3.44 (s, 2H); 7.73-7.79 (m, 3H);7.03-7.15 (m, 2H); 7.21 (d, 2H); 9.69 (s, 1H); 10.42 (s, 1H).

[0409] MS-ESI: 256 [M−H]⁻.

[0410] The starting material was prepared as follows:

[0411] To a suspension of t-BuOK (22.44 g; 0.2 mmol) in THF (300 ml) at−40° C. under argon was added a solution of 4-fluoronitrobenzene (14.1g; 0.1 mmol) and ethyl chloroacetate (14.7 g; 0.12 mmol) in THF (100ml). After 1 hour at −40° C. the mixture was allowed to warm up at −5°C. and 2N HCl (200 ml) was added. After extraction with AcOEt/H₂O theorganic phase was purified by flash chromatography eluting withpetroleum ether/AcOEt to give 20.

[0412]¹HNMR spectrum (CDCl₃): 1.27 (t, 3H); 4.01 (s, 2H); 4.19 (q, 2H);7.07 (dd, 1H); 7.15 (dd., 1H); 8.20 (dd, 1H).

[0413] A mixture of 20 (2.27 g; 0.01 mmol), K₂CO₃ (2.07 g; 0.01 mmol),4-mercaptophenol (1.5 g; 0.01 mmol) in N-methyl pyrrolidone (20 ml) washeated at 80° C. under argon atmosphere for 3 hours. After extractionwith AcOEt/H₂O the organic phase was purified by flash chromatographyeluting with petroleum ether/AcOEt 75/25 to give 19.

[0414] Yield: 81%.

[0415]¹H NMR spectrum (CDCl₃): 1.25 (t, 3H); 3.92 (s, 2H); 4.16 (q, 2H);5.37 (s, 1H); 6.90 (d, 2H); 6.94 (d, 1H); 6.98 (dd, 1H); 7.43 (d, 2H);7.99 (d, 1H).

EXAMPLE 9 6-benzyloxy-1,3-dihydro-2H-indol-2-one

[0416]

[0417] 5-benzyloxy-1,3-dihydro-2H-indol-2-one was prepared as describedin example 2 but using 23 in replacement of 5.

[0418] Yield: 54%.

[0419]¹H NMR spectrum (CDCl₃): 3.47 (s, 2H); 5.06 (s, 2H); 6.53 (d, 1H);6.62 (dd, 1H); 7.10 (d, 1H); 7.32-7.46 (m, 5H); 7.78 (bs, 1H).

[0420] MS-ESI: 240 [M+H]⁺.

[0421] The starting material was prepared as follows:

[0422] Diethylmalonate (3.78 g; 23.6 mmol) was added under argonatmosphere dropwise to a suspension of NaH 60% (0.91 g; 22.8 mmol) inDMSO (40 ml). The mixture was heated at 80° C. for 20 minutes. Aftercooling, 21 (2.7 g; 10 mmol) in solution in DMSO (10 ml) was 4added. Themixture was heated at 100° C. for 20 hours acetic acid (1.4 ml) wasadded and the mixture was extracted with CH₂Cl₂/0.5N HCl. The organicphase was evaporated and purified by flash chromatography eluting withpetroleum ether/AcOEt 80/20 to give 22.

[0423] Yield: 68%.

[0424]¹H NMR spectrum (CDCl₃): 1.28 (t, 6H); 3.36 (s, 1H); 4.21 (q, 2H);5.12 (s, 2H); 7.23 (dd, 1H); 7.35-7.45 (m, 6H); 7.66 (d, 1H).

[0425] A solution of 22 (2.73 g; 7 mmol) and LiCl (0.6 g; 14 mmol) inDMSO (30 ml) and H₂O (0.13 ml) was heated at 80° C. overnight. Themixture was extracted with AcOEt/sat NaCl to give after evaporation ofthe organic phase 23 as an oil which was used without furtherpurification.

[0426] Yield: 32%.

[0427]¹H NMR spectrum (CDCl3): 1.25 (t, 3H); 3.93 (s, 2H); 4.20 (q, 2H);5.12 (s, 2H); 7.17-7 (m, 3H); 7.35-7 (m, 4H); 7.65 (dd, 1H).

EXAMPLE 10 6-(3-aminobenzyloxy)-1,3-dihydro-2H-indol-2-one

[0428]

[0429] A mixture of 24 (0.129 g; 0.454 mmol) and Fe (0.127 g; 2.27 mmol)in MeOH (3 ml) and 12N HCl (1 ml) was heated at 80° C. for 1 h 30. Afterevaporation and dilution with water, the mixture was neutralised to pH7.5 with sat NaHCO₃ and extracted with AcOEt. The organic phase wasevaporated and purified by flash chromatography eluting with petroleumether/AcOEt 50/50 to give after evaporation an oil which was trituratedwith ether and pentane to give6-(3-aminobenzyloxy)-1,3-dihydro-2H-indol-2-one as a solid.

[0430] Yield: 30%.

[0431]¹H NMR spectrum (DMSOd₆): 3.63 (s, 2H); 4.91 (s, 2H); 5.22 (bs,2H); 6.42 (d, 1H); 6.48-6.57 (m, 3H); 6.62 (m, 1H); 7.01 (dd, 1H); 7.07(d, 1H); 10.31 (s, 1H).

[0432] MS-ESI: 255 [M+H]⁺.

[0433] The starting material was prepared as follows:

[0434] A mixture of 26 (0.224 g; 1.5 mmol), K₂CO₃ (0.228 g; 1.65 mmol)and 25 (0.558 g; 1.95 mmol) in DMF (4 ml) was stirred under argonatmosphere for 2 days. The mixture was extracted with H2O/AcOEt and theorganic phase evaporated and purified by flash chromatography elutingwith petroleum ether/AcOEt 30/70 to give 24.

[0435] Yield: 40%.

[0436]¹H NMR spectrum (DMSOd₆): 3.37 (s 2H); 5.25 (s, 2H); 6.49 (d, 1H);6.60 (dd, 1H); 7.11 (d, 1H); 7.71 (dd, 1H); 7.91 (d, 1H); 8.20 (d, 1H);8.30 (s, 1H); 10.38 (s, 1H).

EXAMPLE 11 5-(3-N-glutaminylaminobenzyloxy)-1,3-dihydro-2H-indol-2-one

[0437]

[0438] 5-(3-N-glutaminylaminobenzyloxy)-1,3-dihydro-2H-indol-2-one wasprepared described in example 4 starting from 27.

[0439] Yield: 42%.

[0440]¹H NMR spectrum (DMSOd₆+AcOd₄): 2.04-2.16 (m, 2H); 2.36-2.45 (m,2H); 3.37 (s, 2H); 4.03 (t, 1H); 5.09 (s, 2H); 6.48 (d, 1H); 6.55 (dd,1H); 7.08 (d, 1H); 7.19 (d, 1H); 7.37 (dd, 1H); 7.60 (d, 1H); 7.69 (d,1H); 10.30 (s, 1H); 10.64 (s, 1H).

[0441] MS-ESI:382 [M−H]⁻.

[0442] The starting material was prepared using the same method asdescribed for 10 in Example 4 but starting from6-(3-aminobenzyloxy)-1,3-dihydro-2H-indol-2-one (Example 10.)

[0443] Yield: 69%.

[0444]¹H NMR spectrum (DMSOd₆): 1.4(s, 9H); 1.8-1.96 (m, 21); 2.27-2.34(m, 2H); 3.38 (s, 2H); 4.08-4.31 (m, 3H); 5.07 (s, 2H); 6.46 (d, 1H);6.56 (dd, 1H); 7.08-7.14 (m, 2H); 7.31 7.45 (m, 4H); 7.58 (d; 1H);7.68-7.77 (m, 3H); 7.91 (d, 2H); 10.09 (s, 1H); 10.33 (s, 1H)

EXAMPLE 12 6-benzyloxy-N-methyl-1,3-dihydro-2H-indol2-one

[0445]

[0446] A mixture of 6-benzyloxy-1,3-dihydro-2H-indol-2-one (Example 9)(0.12 g; 0.5 mmol), K₂CO₃ (0.07 g; 0.5 mmol) and CH₃I (0.031 ml) inacetone (5 ml) was refluxed under argon atmosphere for 6 hours. Afterevaporation to dryness, the residue was purified by flash chromatographyeluting with petroleum ether/AcOEt 60/40 to give6-benzyloxy-N-methyl-1,3-dihydro-2H-indol-2-one.

[0447] Yield: 31%.

[0448]¹H NMR spectrum: 3.17 (s, 3H); 3.46 (s, 2H); 5.09 (s, 2H); 6.50(d, 1H); 6.62 (dd, 1H); 7.12 (d, 1H); 7.31-7.49 (m, 5H).

[0449] MS-ESI: 254 [M+H]⁺.

EXAMPLE 13 4-benzyloxy-1,3-dihydro-2H-indol-2-one

[0450]

[0451] To a solution of chlorine (1.47 g; 0.021 mmol) in CH₂Cl₂ (37 ml)at −70° C. was added under argon ethyl methylthioacetate (2 ml; 0.021mmol) in CH₂Cl₂ (10 ml). After stirring for 5 minutes, 29 (8.35 g; 0.042mmol) in solution in CH₂Cl₂ (40 ml) was added dropwise. The mixture wasstirred at −70° C. for 1 hour, triethylamine (4.68 ml; 0.034 mmol) wasadded. After 30 minutes, the mixture was extracted, the organic phasewas evaporated and purified by flash chromatography, eluting withCH₂Cl₂/AcOEt 90/10 to give a mixture of 30 and 31, as a side product

[0452] The mixture of 30 and 31 (0.74 g; 2.59 mmol) in solution in EtOH(20 ml) was treated with Ni Raney (2 g) at room temperature for 2 hours.After filtration of the catalyst, the filtrate was evaporated andpurified by flash chromatography, eluting with petroleum ether/AcOEt60/40 to give 4-benzyloxy-1,3-dihydro-2H-indol-2-one.

[0453]¹H NMR spectrum (CDCl₃): 3.53 (s, 2H); 5.1 (s, 2H); 6.5-6.7 (m,2H); 7.1-7.5 (m, 6H).

[0454] MS-ES: 240 [M+H]⁺.

EXAMPLE 14 5-(4-phosphonophenylsulfanyl)-1,3-dihydro-2H-indol-2-one

[0455]

[0456] A solution of 32 (0.275 g; 0.6 mmol) and TFA (1.5 ml) in CH₂Cl₂(15 ml) was stirred at 0° C. for 10 minutes and at room temperature for15 minutes. After evaporation to dryness, the residue was purified onOASIS resin eluting with a gradient of CH₃CN/H₂O 0-30% to give5-(4-phosphonophenylsulfanyl)-1,3-dihydro-2H-indol-2-one.

[0457] Yield: 63%.

[0458]¹H NMR Spectrum (DMSOd₆+AcOD₄): 3.48 (s, 2H); 6.85 (d, 1H);7.1-7.4 (m, 7H).

[0459] MS-ESI: 336 [M−H]⁻. Elemental analysis Found C 49.10 H 3.68 N4.45 S 9.19 C₁₄H₁₂NO₅SP, Requires C 49.07 H 3.71 N 4.09 S 9.36 0.3 H₂O

[0460] The starting material was prepared as follows:

[0461] To a solution of5-(4-hydroxyphenylsulfanyl)-1,3-dihydro-2H-indol-2-one (Example 8)(0.257 g; 1 mmol) and 1H-tetrazole (0.21 g; 3 mmol) in a mixture of DMF(2 ml) and THF (2 ml) was added under argon atmosphere di-tert-butyldiethylphosphoramidite (560 μl; 2 mmol). After stirring for one hour,the mixture was cooled to −70° C. and magnesium peroxyphtalate (0.544 g;1.1 mmol) was added portionwise. The mixture was stirred at −70° C. forone hour and sat NaHCO₃ (15 ml) was added. After 15 minutes, the mixturewas extracted with AcOEt. The organic phase was evaporated and purifiedby flash chromatography eluting with CH₂Cl₂/EtOH 98/2 to give 1.

[0462] Yield: 61%.

[0463]¹H NMR Spectrum (DMSOd₆): 1.44 (m, 9H); 3.50 (s, 2H); 6.86 (d,1H); 7.1-7.4 (m, 6H).

[0464] MS-ESI: 448 [M−H]⁻.

1. The use of a compound of Formula (I) for the manufacture of amedicament to inhibit and/or reverse and/or alleviate symptom ofangiogenesis and/or any disease state associated with angiogenesis,wherein:

X is selected from: —O—, —S—, —S(O)—, —S(O₂)—, —N(R₅)—, —C(O)—,—C(O)N(R₅)—, —N(R₅)C(O)—, —S(O₂)N(R₅)—, or —N(R₅)S(O₂)—; R₁ isindependently selected from: amino, halo, hydroxy, —OPO₃H₂, C₁₋₄alkyl,or C₁₋₄alkoxy, wherein the amino group is optionally substituted by anamino acid residue and the hydroxy group is optionally esterified; R₂ isselected from: hydrogen or C₁₋₄alkyl; R₃ is selected from: hydrogen,halo, hydroxy, hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, carboxy,carboxyC₁₋₄alkyl, C₁₋₄alkanoyl, C₁₋₄alkanoylC₁₋₄alkyl, carbamoyl,carbamoylC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₄alkoxycarbonylC₁₋₄alkyl, C₁₋₄alkoxycarbonylamino, amino,N-C₁₋₄alkylamino, NN-diC₁₋₄alkylamino, aminoC₁₋₄alkyl,N-C₁₋₄alkylaminoC₁₋₄alkyl, NN-diC₁₋₄alkylaminoC₁₋₄alkyl, ureido, orC₁₋₄alylureyleno; R₄ is independently selected from: C₁₋₄alkyl,C₁₋₄alkoxy or halo; R₅ is selected from: hydrogen or C₁₋₄alkyl; n is 0or 1; p is 0, 1, 2 or 3; and q is 0, 1 or 2; or a salt, pro-drug orsolvate thereof:
 2. The use of a compound according to claim 1, or asalt, pro-drug or solvate thereof, wherein X is —O—, —S—, —S(O)—, or—S(O₂)—.
 3. The use of a compound according to claim 1 or claim 2, or asalt, pro-drug or solvate thereof, wherein R³ is hydrogen.
 4. The use ofa compound according to any one of the preceding claims, or a salt,pro-drug or solvate thereof, wherein R¹ is amino, hydroxy, —OPO₃H₂, orC₁₋₄alkoxy, wherein the amino group is optionally substituted by anamino acid residue and the hydroxy group is optionally esterified. 5.The use of a compound according to claim 4, or a salt, pro-drug orsolvate thereof, wherein R¹ is amino substituted by an amino acidresidue or is an esterified hydroxy group.
 6. The use of a compoundaccording to claim 5, or a salt, pro-drug or solvate thereof, wherein R₁is amino substituted by an amino acid residue and the amino acid residueis derived from glutamic acid, serine, threonine, arginine, glycine,alanine, β-alanine or lysine.
 7. The use of a compound according toclaim 4, or a salt, pro-drug or solvate thereof, wherein R¹ isC₁₋₄alkoxy.
 8. The use of a compound of Formula (IIa), or apharmaceutically-acceptable salt, pro-drug or solvate thereof, as amedicament,

wherein: n, q, X, R₁, R₂, R₃, R₄ and R₅ are as defined in claim 1; and pis 1, 2 or 3 with the proviso that: (i) when p is 1, R₁ cannot be haloor methyl, and when p is 2, (R₁)_(p) cannot be di-halo or di-methyl;(ii) when X is —S(O₂)N(R₅)—, —N(R₅)S(O₂)—, —N(R₅)C(O)— or —C(O)—, n is 0or 1, R₂ is hydrogen, R₃ is hydrogen, q is 0 or q is 1 and R₄ is5-chloro and R⁵ is hydrogen, then (R₁)_(p) cannot be 2-methoxy,3-methoxy, 4-methoxy, 4-nitro, 4-hydroxy, 4-amino, 3-chloro-4-methoxy or3-chloro-4-ethoxy; and (ii) when X is linked at the 7-position of theoxindole ring, X is —O—, n is 0, R₂ is hydrogen, R₃ is hydrogen ormethyl and q is 0, then (R₁)_(p) cannot be 2-methoxy, 2-amino, or3,4,5-tri-methoxy; or a pharmaceutically-acceptable salt, pro-drug orsolvate thereof.
 9. A compound of Formula (IIa) as defined in claim 8,or salt, pro-drug or solvate thereof.
 10. A compound of Formula (III),wherein:

X is selected from: —S—, —S(O)—, or —S(O₂)—; and wherein R¹, R², R³, R⁴,n, p and q are as defined in claim 1; with the proviso that thefollowing compounds are excluded:7-(phenylsulfanyl)-1,3-dihydro-2H-indol-2-one;7-(2-chlorophenylsulfanyl)-1,3-dihydro-2H-indol-2-one;7-(4-chlorophenylsulfanyl)-1,3-dihydro-2H-indol-2-one;7-(benzylsulfanyl)-1,3-dihydro-2H-indol-2-one;7-(phenylsulfinyl)-1,3-dihydro-2H-indol-2-one;7-(2-chlorophenylsulfinyl)-1,3-dihydro-2H-indol-2-one;7-(4-chlorophenylsulfinyl)-1,3-dihydro-2H-indol-2-one;7-(phenylsulfonyl)-1,3-dihydro-2H-indol-2-one; and7-(4-chlorophenylsulfonyl)-1,3-dihydro-2H-indol-2-one; or a salt,pro-drug or solvate thereof. 11 A compound of Formula (V), wherein:

wherein R¹, R², R³, R⁴, R⁵, n, p and q are as defined in claim 1; withthe proviso that: (i) when —(CH₂)_(n)O— is linked at the 4-position ofthe oxindole ring, n is 0, p is 0 and R₂ and R₃ are each independentlyhydrogen and q is 1 then R₄ cannot be 7-chloro; (ii) when —(CH₂)_(n)O—is linked at the 5-position of the oxindole ring, n is 0 or 1, R₂ ishydrogen or methyl, R₃ is hydrogen and q is 0, then p cannot be 0 and(R₁)_(p) cannot be 2-chloro or 4-chloro; (iii) when —(CH₂)_(n)O— islinked at the 6-position of the oxindole ring, n is 1, p is 0, R₂ ishydrogen or methyl, R₃ is hydrogen and q is 1 then R₄ cannot be5-methoxy; and (iv) when —(CH₂)_(n)O— is linked at the 7-position of theoxindole ring, n is 0 or 1, R₂ is hydrogen or methyl, R₃ is hydrogen andq is 0, then p cannot be 0 and (R₁)_(p) cannot be 2-chloro, 2-fluoro,2-amino, 2,6-dichloro or 3,4,5-trimethoxy; or a salt, pro-drug orsolvate thereof. 12 A compound according to claim 9 or claim 10, or asalt, pro-drug or solvate thereof, wherein R³ is hydrogen.
 13. Acompound according to any one of claims 9 to 11, or a salt, pro-drug orsolvate thereof, wherein R¹ is amino, hydroxy, —OPO₃H₂, or C₁₋₄alkoxy,wherein the amino group is optionally substituted by an amino acidresidue and the hydroxy group is optionally esterified.
 14. A compoundaccording to claim 13, or a salt, pro-drug or solvate thereof, whereinR¹ is amino substituted by an amino acid residue or C₁₋₄alkoxy.
 15. Acompound according to claim 14, or a salt, pro-drug or solvate thereof,wherein R¹ is amino substituted by an amino acid residue and the aminoacid residue is derived from glutamic acid, serine, threonine, arginine,glycine, alanine, β-alanine or lysine.
 16. A compound according to claim13, or a salt, pro-drug or solvate thereof, wherein R¹ is C₁₋₄alkoxy.17. A compound selected from:5-(phenylsulfanyl)-1,3-dihydro-2H-indol-2-one;5-(4-aminophenoxy)-1,3-dihydro-2H-indol-2-one;5-(4-aminophenylsulfanyl)-1,3-dihydro-2H-indol-2-one;5-(4-hydroxyphenylsulfanyl)-1,3-dihydro-2H-indol-2-one; and6-(3-aminobenzyloxy)-1,3-dihydro-2H-indol-2-one;5-(4-N-glutaminylaminophenoxy)-1,3-dihydro-2H-indol-2-one;5-(4-N-Serylaminophenoxy)-1,3-dihydro-2H-indol-2-one;5-(4-N-Glycylaminophenoxy)-1,3-dihydro-2H-indol-2-one;5-(4-N-glutaminylaminophenylsulfanyl-1,3-dihydro-2H-indol-2-one;5-(3-N-glutaminylaminobenzyloxy)-1,3-dihydro-2H-indol-2-one; and5-(4-phosphonophenylsulfanyl)-1,3-dihydro-2H-indol-2-one; or a salt,prodrug or solvate thereof.
 18. A pharmaceutical composition comprisinga compound according to any one of claims 9 to 17 or apharmaceutically-acceptable salt, pro-drug, or solvate thereof, inadmixture with a pharmaceutically-acceptable diluent or carrier.
 19. Theuse of a compound of Formula (I) as defined in claim 1, or salt,pro-drug or solvate thereof, in the manufacture of a medicament foradministration in divided doses for use in the production of ananti-tumour effect in a warm-blooded animal.
 20. A process for preparinga compound of Formula (I), or salt, pro-drug or solvate thereof, whichprocess (wherein n, p, q, X, R₁, R₂, R₃, R₄ and R₅ are unless otherwisespecified as defined in Claim I) comprising: a) for compounds of Formula(I) wherein X is —O—, —S— or —N(R₅)—, reacting a compound of Formula (A)with a compound of Formula (B),

 wherein L₁ is a leaving group; b) for compounds of Formula (I) whereinR₂ is hydrogen, reduction of a compound of Formula (C), wherein R₆ ishydrogen or an alkyl chain,

c) for compounds of Formula (I) wherein R₂ is C₁₋₄alkyl, reacting acompound of Formula (I) wherein R₂ is hydrogen with a suitablealkylhalide; d) for compounds of Formula (I) wherein R₂ is hydrogen andR₃ is hydrogen reacting a compound of Formula (D) with analkylthioacetate, followed by reduction,

e) for compounds of Formula (I) wherein X is —S(O₂)N(R₅)—, reacting acompound of Formula E) with an amine of Formula (F),

 wherein L₃ is a displaceable group; f) for compounds of Formula (I)wherein X is —N(R₅)S(O₂)—, reacting an amine of Formula (G) with acompound of Formula (H),

 wherein L₃ is a displaceable group; g) for compounds of Formula (I)wherein X is —S(O)—, —S(O₂)—, oxidising a compound of Formula (J),

and thereafter if necessary: i) converting a compound of the Formula (I)into another compound of the Formula (I); ii) removing any protectinggroups; iii) forming a salt, pro-drug or solvate.